JP2021119131A - Pharmaceutical composition containing benzene derivative - Google Patents

Abstract

To provide pharmaceutical compositions containing a compound having a neural protecting and/or repairing action.SOLUTION: Provided is a pharmaceutical composition containing, for example, a compound having the following structural formula or a salt thereof. Since the pharmaceutical composition has a strong neural protecting and/or repairing action, it can be a therapeutic agent for neuropathy (for example, chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome, polyarteritis nodosa, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, peripheral neuropathy associated with chemotherapy drug administration, peripheral neuropathy associated with Charcot-Marie-Tooth disease and the like).SELECTED DRAWING: Figure 1

Description

The present disclosure is based on the following general formula (I).

(In the formula, all symbols have the same meaning as described below.)
The present invention relates to a pharmaceutical composition or the like containing the compound represented by (1) or a salt thereof (hereinafter, may be abbreviated as the compound of the present invention).

The nervous system is roughly divided into the central nervous system and the peripheral nervous system. Among them, the peripheral nervous system connects the brain and spinal cord with the peripheral body and is responsible for nerve transmission. The peripheral nervous system can be classified into the somatic nervous system (cerebral spinal nervous system) and the autonomic nervous system. Furthermore, the somatic nervous system is divided into the cranial nerves and the spinal nerves. In addition, when the somatic nervous system is functionally classified, those that transmit nerve signals (excitement) generated from sensory receptors to the central nervous system are classified into afferent or sensory nerve fibers, whereas the brain and Those that transmit nerve signals from the spinal cord to effectors such as muscles and glands are classified as efferent or motile nerve fibers. Cranial nerves are the peripheral nerves that emerge from the brain and are known to consist of 12 pairs, some of which are sensory, some of which are motile, and some of which are mixed nerve fibers. The first to twelfth nerve pairs are called olfactory nerve, optic nerve, moving eye nerve, pulley nerve, trigeminal nerve, abduction nerve, facial nerve, internal ear nerve, lingual nerve, stray nerve, accessory nerve, and sublingual nerve, respectively. Of these, the nerves composed of sensory or mixed nerve fibers are known to be the olfactory nerve, the optic nerve, the trigeminal nerve, the facial nerve, the vestibulocochlear nerve, the glossopharyngeal nerve, and the vagus nerve. The spinal nerves are peripheral nerves originating from the spinal cord, and 31 pairs of left and right are known, 8 pairs of cervical nerves, 12 pairs of thoracic nerves, 5 pairs of lumbar nerves, 5 pairs of sacral nerves and 1 pair of caudal nerves. .. The spinal nerves are all composed of mixed nerve fibers, and include sensory fibers (dorsal roots) that go to the skin and the like and motor fibers (ventral roots) that go to skeletal muscles.

Sensory nerve fibers, that is, sensory nerves, have the function of accurately transmitting stimuli such as light, sound, temperature, and contact received by sensory receptors such as the visual organs, auditory organs, olfactory organs, taste organs, and skin to the central nervous system. Is responsible for. The neural signals transmitted to the central nervous system are finally transmitted to each sensory area of the cerebral cortex, for example, the visual cortex, the auditory area, etc., and the sensation is normally recognized. However, these sensory nerves are affected by axons, myelin sheaths, Schwann cells, etc. due to, for example, viral infection, tumor, cancer, diabetes, ischemia, trauma, compression, drugs, radiotherapy, etc., resulting in cell death or demyelination. Various neuropathy such as myelin may be caused. As a result, accurate nerve transmission is not performed in the impaired sensory nerve, and thus diseases such as deafness and neuropathic pain develop. In addition to these, peripheral neuropathy in which not only specific sensory nerves but also various peripheral nerves including sensory nerves are simultaneously damaged due to causes such as metabolic diseases, autoimmune diseases, trauma, drug addiction, etc. be. The disease can damage a single nerve, two or more nerves in separate areas, or multiple nerves at the same time. Symptoms include peripheral stinging, numbness, burning sensation, decreased joint proprioception, decreased vibration sensation, pain (including neuropathic pain), dysesthesia, coldness or burning, and are very complex. It is diverse.

However, the above-mentioned peripheral nervous system diseases are diseases whose pathogenesis is unknown or physical damage to nerves. Therefore, when treating them, the symptomatic treatment is mainly aimed at improving the symptoms. Few clinically useful drugs are known that provide symptomatic treatment and provide curative treatment that acts directly on the damaged nervous system.

An object of the present invention is to provide a pharmaceutical composition containing a compound having a neuroprotective and / or repairing action.

As a result of diligent studies to solve the above problems, the present inventors have found that the compound represented by the following general formula (I) or a pharmaceutical composition containing a salt thereof has a strong neuroprotective and / or repairing action. Found to have.
That is, the present invention, in one aspect,
[1] General formula (I)

[In the formula, R ¹ is (1) -R ^11- COOR ¹² , (2) -R ^13- CONR ¹⁴ R ¹⁵ , (3) -R ^17- CN, (4) -R ^18- CONHS (O). _2- R ¹⁹ , (5) -R ^20- CycD, or

(In the group, ring1 represents a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle, and R ¹⁰¹ is (1) a halogen atom, (2) a C1 to 4 alkyl group, or (3) a C1 to 4 haloalkyl group. , N represents an integer from 0 to 3, and when n is 2 or more, a plurality of R ^101s may be the same or different.)
R ¹¹ , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ²⁰ are independently (1) C1-6 alkylene groups, which may be substituted with 1 to 3 halogen atoms, (2). ) Represents a C2-6 alkenylene group optionally substituted with 1 to 3 halogen atoms, or (3) a C2-6 alkynylene group optionally substituted with 1 to 3 halogen atoms. When the alkylene group, alkenylene group or alkynylene group is a branched chain, two C1-2 alkyl groups branched from the same carbon atom may be combined to form a saturated carbon ring of C3-5.
R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁹ independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, respectively.
CycD stands for triazole or tetrazole
R ² represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, p represents an integer from 0 to 3, and when p is 2 or more, a plurality of Rs. ² may be the same or different,
X represents (1) CH ₂ or (2) oxygen atom,
L ¹ is (1) a 1-4 ^R C3-7 alkylene group which may linear substituted with ^L1a, (2) a 1-4 ^R good linear be substituted with ^L1a C3~7 alkenylene group, optionally substituted by (3) 1-4 C3~7 alkynylene group which may straight optionally substituted with ^{R L1a} or (4) (1-2 ^{R L1a,} good represents a linear chain of C1~3 alkylene group) -O- (1 to 2 amino C1~3 alkylene group which may straight optionally substituted with ^{R L1a),}
R ^L1a is (1) halogen atom, (2) represents a hydroxyl group, a (3) an oxo group or (4) C1-2 alkyl group, ^a plurality of ^{R L1a} when ^{R L1a} is two or more the same or different from each other at best, further when the two R ^L1a each C1~2 alkyl groups attached to the same carbon atom, the C1~2 alkyl group saturated carbocyclic ring C3~5 together with the carbon atom bonded May form,

Represents a single bond, double bond or triple bond,
R ³ represents (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-2 alkyl group, or (5) a methylidene group, and q represents an integer from 0 to 2.

If is a single bond and q is 2, the plurality of R ^3s may be the same or different, and if at least one R ³ is a methyl group, together with the carbon atoms in the ^{adjacent L 1.} Cyclopropane may be formed,
CycA represents (1) C5-10 monocyclic or bicyclic carbocycles, or (2) 5-10 membered monocyclic or bicyclic heterocycles.
R ⁴ is (1) halogen atom, (2) hydroxyl, (3) C1 -4 alkyl group, (4) C1 -4 haloalkyl group, (5) C1 -4 alkoxy group, (6) C1 -4 haloalkoxy group, (7) a cyano group, or ₍₈₎ -SO 2 _-C1~2 alkyl group,, r represents an integer of 0 to 6, r is not different in the plurality of ^{R 4} when two or more identical respectively May be
L ² represents −R ³¹ −L ³ −R ^32-
L ³ is (1) -NR ^201- S (O)-, (2) -NR ^202- S (O) _2- , (3) -NR ^203- C (O)-, (4) -CR ²⁰⁴ Represents (OH)-, (5) -NR ^205- , (6) -S (O)-, or (7) -S (O) _2-
R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ , and R ²⁰⁵ each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group. Among them, the alkyl group or haloalkyl group is substituted with (1) a hydroxyl group, (2) an oxo group, (3) a C3 to 6 monocyclic carbocycle, or (4) a 3 to 6 member monocyclic heterocycle. May be
R ³¹ and R ³² may each be independently substituted with (1) a bond or (2) 1-3 substituents selected from the group consisting of halogen atoms, hydroxyl groups and oxo groups. Represents a C1 to 3 alkylene group
CycB represents (1) C5-10 monocyclic or bicyclic carbocycles, or (2) 5-10 membered monocyclic or bicyclic heterocycles.
R ⁵ is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkoxy group, (4) C2-6 alkynyl group, (5) C1-6 haloalkyl group, (6) C2. ~ 6 Haloalkenyl groups, (7) C2-6 haloalkynyl groups, (8) C1-6 alkoxy groups, or (9) C1-6 haloalkoxy groups, where t represents an integer from 0 to 6 and t is When it is 2 or more, the plurality of R ^5s may be the same or different. ], A pharmaceutical composition containing the compound or a salt thereof.
[1-1] The pharmaceutical composition according to the above [1], which further contains a pharmaceutically acceptable carrier.
[2] In the general formula (I),

But, (1) = CH- (1~2 amino ^R C2-6 alkylene group which may linear substituted with ^{L1a) -, (2) -} ( optionally substituted with one to two ^{R L1a} C3~7 alkylene group which may linear in) -, or (3) - (1-2 C1~3 alkylene group which may straight optionally substituted with ^{R L1a)} -O- (1-2 is also C1~3 alkylene group which may linear) be substituted with number of ^{R L1a} ((1) ^{R L1a} is to (3) as defined above [1] wherein), wherein [1] The pharmaceutical composition according to
[3] The pharmaceutical composition according to any one of [1] or [2] above, wherein ^{R 1} is −R ¹¹ −COOR ^12.
[4] Described in any of the above [1] to [3], wherein ^{L 2} is (1) -NR ^202- S (O) _2- or (2) -CR ²⁰⁴ (OH) -CH _2-. Pharmaceutical composition,
[5] The pharmaceutical composition according to any one of the above [1] to [4], wherein CycA is a C5-6 monocyclic carbocycle.
[6] The pharmaceutical composition according to any one of the above [1] to [5], wherein CycB is a C5-6 monocyclic carbocycle.
[7] The general formula (I) is the general formula (I-1).

[In the formula, R ^11-1 represents a C2-4 alkylene group, L ^1-1 represents a linear C3-4 alkylene group optionally substituted with 1-2 R ^{L1a , CycA 1} and CycB ¹ are each independently a C5~6 monocyclic carbocyclic ^{ring, L 2-1} are, (1) -NH-S ( O) 2 -, or (2) -CH (OH) -CH 2 -Is represented, and other symbols have the same meaning as [1] above. ], The pharmaceutical composition according to any one of the above [1] to [6].
[8] The pharmaceutical composition according to any one of [1] to [7] above, wherein X is an oxygen atom.
[9] The compound represented by the general formula (I) or a salt thereof is
(1) 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(2) 3- [2-[(3S) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid,
(3) 3- [2-[(3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid,
(4) 3- [2-[(E, 3R) -5- [4- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(5) 3- [2-[(E, 3R) -5- [3- (cyclopentylsulfonylamino) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(6) 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -2-methylphenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(7) 4- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] butanoic acid,
(8) 3- [2-[(E) -4- [3- (benzenesulfonamide) phenyl] -2-hydroxybut-3-enoxy] phenyl] propanoic acid,
(9) (R) -3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enyl] phenyl] propanoic acid,
(10) (S) -3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enyl] phenyl] propanoic acid,
(11) 3- [2-[(E) -5-[3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid,
(12) 3- [2- [5- [3- (benzenesulfonamide) phenyl] pentoxy] phenyl] propanoic acid,
(13) 3- [2-[(3S) -3-hydroxy-5-[3-[(1R) -1-hydroxy-2-phenylethyl] phenyl] pentoxy] phenyl] propanoic acid,
(14) 3- [2-[(3S) -3-hydroxy-5-[3-[(1S) -1-hydroxy-2-phenylethyl] phenyl] pentoxy] phenyl] propanoic acid,
(15) 3- [2- [2- [2- [3- (benzenesulfonamide) phenyl] ethoxy] ethoxy] phenyl] propanoic acid,
(16) 3- [2- [6- [3- (benzenesulfonamide) phenyl] -4-oxohexyl] phenyl] propanoic acid, or (17) 3- [2- [5- [3- (benzenesulfonamide) benzenesulfon) The pharmaceutical composition according to the above [1], which is amide) phenyl] -3,3-difluoropentoxy] phenyl] propanoic acid or a salt thereof.
[10] The pharmaceutical composition according to any one of [1] to [9] above, for neuroprotection and / or repair.
[11] The neuroprotection and / or repair is neuroprotection and / or repair via glial cells (eg, microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.), as described above [10]. ] Described pharmaceutical composition,
[12] The pharmaceutical composition according to the above [11], wherein the neuroprotection and / or repair via glial cells is neuroprotection and / or repair by promoting myelination of Schwann cells.
[13] The pharmaceutical composition according to any one of [1] to [12] above, which is a prophylactic and / or therapeutic agent for neuropathy.
[14] The pharmaceutical composition according to the above [13], wherein the neuropathy is a peripheral neuropathy.
[15] Peripheral neuropathy is associated with chronic inflammatory demyelinating polyneuritis, Gillan Valley syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, and chemotherapy drug administration. The pharmaceutical composition according to the above [14], which is a peripheral neuropathy or a peripheral neuropathy associated with Charcot-Marie-Tooth disease.
[2-1] A Schwann cell differentiation-promoting agent containing the compound represented by the general formula (I) described in the above [1] or a salt thereof.
[2-1-1] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] Schwann cell differentiation promoter containing propanoic acid or a salt thereof ,
[2-2] A neuroprotective and / or repair agent containing the compound represented by the general formula (I) described in the above [1] or a salt thereof.
[2-2-1] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] Neuroprotection and / or containing propanoic acid or a salt thereof Restorative agent,
[2-2-2] Neuroprotection and / or repair is neuroprotection and / or repair via glial cells (eg, microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.). , The agent according to any one of the above [2-2] or [2-2-1].
[2-2-3] The agent according to the above [2-2-2], wherein the neuroprotection and / or repair via glial cells is neuroprotection and / or repair by promoting myelination of Schwann cells.
[2-3] A prophylactic and / or therapeutic agent for neuropathy containing the compound represented by the general formula (I) described in the above [1] or a salt thereof.
[2-3-1] 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] Prevention of neuropathy containing propanoic acid or a salt thereof and / Or therapeutic agent,
[2-3-2] The agent according to any one of the above [2-3] or [2-3-1], wherein the neuropathy is a peripheral neuropathy.
[2-3-3] Peripheral neuropathy includes chronic inflammatory demyelinating polyneuritis, Gillan Valley syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, chemotherapy The agent according to the above [2-3-2], which is a peripheral neuropathy associated with drug administration or a peripheral neuropathy associated with Charcot-Marie-Tooth disease.
Etc.

The pharmaceutical composition containing the compound of the present invention has a strong neuroprotective and / or repairing action, and is therefore useful for the treatment of neuropathy, for example, peripheral neuropathy.

In the streptozotocin model, the nociception thresholds when the compounds of Examples 11, 36, 37 and 84 were administered at a dose of 0.3 mg / kg (the vertical axis represents the nociception threshold and the horizontal axis represents the post-streptozotocin administration). Represents the number of days elapsed.)

Hereinafter, the present invention will be described in detail.
In the present invention, the 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle refers to a monocyclic saturated heterocycle containing at least one nitrogen atom, for example, aziridine, azetidine, pyrridine, imidazolidine, and the like. Triazolidine, tetrazolidine, pyrazolidine, piperidine, piperidine, perhydropyrimidine, perhydropyridazine, tetrahydrooxazolidine (oxazolidine), tetrahydroisoxazolidine (isooxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydroflazan, tetrahydro Examples thereof include oxadiazol (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrothiazolidine (thiathiazolidine), tetrahydrothiazine, tetrahydrothiazidine, morpholin, and thiomorpholin.

In the present invention, the halogen atom means fluorine, chlorine, bromine, iodine and the like.

In the present invention, the C1-4 alkyl group includes a linear or branched C1-4 alkyl group, for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert. -Butyl is mentioned.

In the present invention, the C1-4 haloalkyl group refers to a group in which a linear or branched C1-4 alkyl group is substituted with one or more halogen atoms, for example, fluoromethyl, chloromethyl, bromomethyl. , Iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4, Examples thereof include 4,4-trifluorobutyl or 4-bromobutyl.

In the present invention, the C1-6 alkylene group includes a linear or branched C1-6 alkylene group, and examples thereof include methylene, ethylene, propylene, butylene, pentylene, hexanylene or isomers thereof. Be done.

In the present invention, the C2-6 alkenylene group includes a linear or branched C2-6 alkenylene group, and examples thereof include ethenylene, propenylene, butenylene, pentenylene, hexenylene, and isomers thereof. ..

In the present invention, the C2-6 alkynylene group includes a linear or branched C2-6 alkynylene group, and examples thereof include ethynylene, propynylene, butynylene, pentynylene, hexynylene, and isomers thereof. ..

In the present invention, examples of the linear C3 to 7 alkylene group include propylene, butylene, pentylene, hexanylene or heptanylene.

In the present invention, the linear C3-7 alkenylene group includes, for example, propenylene, butenylene, pentenylene, hexenylene, heptenylene, or an isomer thereof.

In the present invention, the linear C3-7 alkynylene group includes, for example, propynylene, butynylene, pentynylene, hexynylene, or isomers thereof.

In the present invention, the C1-2 alkyl group refers to methyl or ethyl.

In the present invention, examples of the saturated carbocycles of C3 to 5 include cyclopropane, cyclobutane, and cyclopentane.

In the present invention, the C5-10 monocyclic or bicyclic carbocycles are, for example, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptane, cyclooctene, cyclopentadiene, cyclohexadiene. , Cycloheptadiene, cyclooctane, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene.

In the present invention, a 5- to 10-membered monocyclic or bicyclic heterocycle is a 5- to 10-membered monocyclic or bicyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom. Ring, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, Frazan, Oxazole, Oxazole, Oxazole, Oxazole, Oxazolepine, Thiasiazol, Thiazin, Thiasiazine, Thiazepine, Thiasiazepine, Indol, Isoindole, Indridin, Benzofuran, Isobenzofuran, Benzothiophene, Isobenzothiophene, Dithianaphthalene, Indazole, Kinolin, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthylidine, quinoxazole, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, chromen, benzofrazan, benzothiasizole, benzotriazole, pyrrolin, pyrrolidine, imidazoline, imidazolidine, triazoline, Triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazin, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine , Perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiophene, tetrahydrothiophene , Dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazoledin), dihydrothiazole, tetrahydrothiazole (thiazolidine) ), Dihydroisothiazole, Tetrahydro Isothiazole (isothiazolidine), dihydroflazan, tetrahydrofuran, dihydrooxadiazole, tetrahydrooxazazole (oxadiazolidine), dihydrooxane, tetrahydrooxane, dihydrooxadiazine, tetrahydrooxadiadin, dihydrooxazepine, Tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiaizole, tetrahydrothiazol (thiosiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiazine , Tetrahydrothiaidine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, morpholin, thiomorpholin, oxatian, indolin, isoindrin, dihydrobenzofuran, Perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinazoline, tetrahydroquinoline, perhydroquinoline, Dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxane, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, per. Hydroquinazoline, dihydrocinnoline, tetrahydrosinnoline, perhydrosinnoline, benzothiophene, dihydrobenzoxazine, dihydrobenzothiazine, pyradinomorpholin, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole , Dihydrobenzimidazole, perhydrobenzimidazole, dioxolan, dioxane, dithiolan, dithian, dioxanedan, benzodioxane, chromane, benzodithiolan, benzodithian.

In the present invention, the C1-4 alkoxy groups include linear or branched C1-4 alkoxy groups, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. -Butoxy, tert-Butoxy can be mentioned.

In the present invention, the C1 to 4 haloalkoxy groups refer to groups in which linear or branched C1 to 4 alkoxy groups are substituted with one or more halogen atoms, for example, trifluoromethoxy and trichloromethoxy. , Chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3- Examples thereof include chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy and 1-chlorobutoxy.

In the present invention, examples of the C3 to 6 monocyclic carbocycle include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

In the present invention, the 3- to 6-membered monocyclic heterocycle refers to a 3- to 6-membered monocyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom. Imidazole, triazole, tetrahydropyran, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isooxazole, thiazole, isothiazole, frazane, oxaziazole, oxazine, oxadiazine, thiazazole, thiazine, thiadiazine, Aziridine, azetidine, pyrrolin, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyran, piperidine, dihydropyran, tetrahydropyran, piperazin, dihydropyranidin, tetrahydropyranidin, perhydropyranidin, Dihydropyrandazine, tetrahydropyridazine, perhydropyridazine, oxylan, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, tiylan, thietan, dihydrothiophene, tetrahydropyran, dihydrothiopyran, tetrahydropyran, dihydrooxazole, tetrahydroxazole (oxazolidine) ), Dihydroisoxazole, tetrahydroisoxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofrazan, tetrahydropyran, dihydroxaziazole, tetrahydrooxadi Azol (oxadiazolidine), dihydrooxazine, tetrahydropyran, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiazazole, tetrahydrothiazol (thiadiazolidine), dihydrothiadin, tetrahydrothiadin, dihydrothiazidine, tetrahydrothiadia Examples include gin, morpholin, thiomorpholin, oxatian, dioxoran, dioxane, dithiolan and ditian.

In the present invention, the 5- to 6-membered monocyclic heterocycle refers to a 5- to 6-membered monocyclic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom. Imidazole, triazole, tetrahydropyran, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isooxazole, thiazole, isothiazole, frazane, oxadiazol, oxazine, oxadiazine, thiazazole, thiazine, thiadiazine, Pyrrolin, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolydin, tetrazoline, tetrazolysin, pyrazoline, pyrazolidine, dihydropyran, tetrahydropyran, piperidine, dihydropyran, tetrahydropyran, piperazin, dihydropyranidin, tetrahydropyranidin, perhydropyranidin, dihydropyranidin, tetrahydropyran. Pyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydropyran, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isooxazolidine) ), Dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydroflazan, tetrahydropyran, dihydrooxadazole, tetrahydroxazol (oxadiazolidine), dihydrooxazine, tetrahydroxazine. , Dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiazol, tetrahydrothiasizole (thiazoliazine), dihydrothiazine, tetrahydrothiazine, dihydrothiazine, tetrahydropyranidin, morpholine, thiomorpholin, oxatian, dioxolan, dioxane , Dithiolan, Ditian.

In the present invention, the 5- to 6-membered monocyclic aromatic heterocycle refers to a 5- to 6-membered monocyclic aromatic heterocycle containing a heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom. Examples thereof include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, flazan, oxadiazol and thiaziazole.

In the present invention, the C1 to 3 alkylene groups include linear or branched C1 to 3 alkylene groups, and examples thereof include methylene, ethylene, propylene, and isomers thereof.

In the present invention, the C1-6 alkyl groups include linear or branched C1-6 alkyl groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-. Examples include butyl, tert-butyl, pentyl, hexyl, or isomers thereof.

In the present invention, the C2-6 alkenyl group includes a linear or branched C2-6 alkenyl group, and examples thereof include ethenyl, propenyl, butenyl, pentenyl, hexenyl, or isomers thereof. ..

In the present invention, the C2-6 alkynyl group includes a linear or branched C2-6 alkynyl group, and examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and isomers thereof. ..

In the present invention, the C1-6 haloalkyl group refers to a group in which a linear or branched C1-6 alkyl group is substituted with one or more halogen atoms, for example, fluoromethyl, chloromethyl, bromomethyl. , Iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4, Examples thereof include 4,4-trifluorobutyl, 4-bromobutyl, 1-fluoropentane and 2-chlorohexane.

In the present invention, the C2-6 haloalkenyl group refers to a group in which a linear or branched C2-6 alkenyl group is substituted with one or more halogen atoms, for example, 1-fluoroethenyl. 2-Fluoroethenyl, 2-chloroethenyl, pentafluoroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4,4,4-trifluorobutenyl, 4-bromobutenyl, 1 -Fluoropentenyl, 2-chlorohexenyl can be mentioned.

In the present invention, the C2-6 haloalkynyl group refers to a group in which a linear or branched C2-6 alkynyl group is substituted with one or more halogen atoms, for example, 1-fluoroethynyl, 2 -Fluoroethynyl, 2-chloroethynyl, pentafluoroethynyl, 1-fluoropropynyl, 2-chloropropynyl, 3-fluoropropynyl, 3-chloropropynyl, 4,4,4-trifluorobutynyl, 4-bromobutynyl, 1- Fluoropentinyl and 2-chlorohexynyl can be mentioned.

In the present invention, the C1-6 alkoxy groups include linear or branched C1-6 alkoxy groups, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, and the like. Examples thereof include n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy and isohexyloxy.

In the present invention, the C1-6 haloalkoxy groups refer to groups in which linear or branched C1-6 alkoxy groups are substituted with one or more halogen atoms, for example, trifluoromethoxy and trichloromethoxy. , Chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3- Examples thereof include chloropropoxy, 2,3-dichloropropoxy, 1-fluorobutoxy, 4-fluorobutoxy, 1-chlorobutoxy, 2-fluoropentoxy and 3-chlorohexyloxy.

In the present invention, examples of the linear C2-6 alkylene group include ethylene, propylene, butylene, pentylene and hexanylene.
In the present invention, examples of the linear C3 to 7 alkylene group include propylene, butylene, pentylene, hexanylene and heptanylene.
In the present invention, examples of the linear C1 to 3 alkylene groups include methylene, ethylene and propylene.

In the present invention, examples of the C5-6 monocyclic carbocycle include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

In the present invention, the C2-4 alkylene group includes a linear or branched C2-4 alkylene group, and examples thereof include ethylene, propylene, butylene and isomers thereof.
In the present invention, the C3-4 alkylene group includes a linear or branched C3-4 alkylene group, and examples thereof include propylene, butylene and isomers thereof.

In the present invention

Means single bond, double bond or triple bond, and in the case of double bond, cis or trans form is included.

In the present invention, binding of the orientation of the ^{L 3} is not limited, for example, ^{L 3} is ^-NR 202 -S _{(O) 2} - For, ^{L 2 is, -R 31 -NR 202 -S (O} ) 2 - It may be ^{R 32 or −R 31} −S (O) _2- NR ²⁰² −R ³² .

In the present invention, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene and alkoxy groups include straight or branched chains unless otherwise specified.

In the present invention, when R ³ has a methylene group, the formula is a partial structure in the general formula (I).

[In the formula, all symbols have the same meaning as above. ] Is the following structure

Means to take.

The compound of the present invention is a compound represented by the following general formula (I) or a salt thereof, which has 5 or more atoms between the CycA and benzene rings.

In the present invention, as R ¹ , -R ^11- COOR ¹² is preferable, and -R ^11- COOH is more preferable. Further, as R ¹¹ , C1 to 6 alkylene groups which may be substituted with 1 to 3 halogen atoms are preferable, and C2 to 4 alkylene groups which may be substituted with 1 to 3 halogen atoms are preferable. More preferred.

In the present invention, R ¹

When, as ring1, a 6-membered nitrogen-containing monocyclic saturated heterocycle is more preferable, and morpholine is further preferable.

In the present invention, R ¹⁰¹ is preferably a hydrogen atom.

In the present invention, as R ¹¹ , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ²⁰ , C1 to 6 alkylene groups which may be substituted with 1 to 3 halogen atoms, respectively, are preferable, and 1 to 3 are preferable. More preferred are C2-4 alkylene groups that may be substituted with a single halogen atom.

In the present invention, hydrogen atoms are preferable as ^{R 12} , R ¹⁴ , R ¹⁵ and R ^{19, respectively.}

In the present invention, R ² is preferably a halogen atom or a C1-4 alkyl group.

In the present invention, X is preferably an oxygen atom.

In the present invention, the ^{L 1,} is substituted by (1) 1-4 C3~7 alkylene group which may straight optionally substituted with ^{R L1a} or (2) (1-2 ^{R L1a,} C1 -3 alkylene group which may straight though) -O- (1 to 2 amino ^R C1 -3 alkylene group which may straight optionally substituted with ^L1a) is preferably, 1 to 4 ^{R L1a} A straight chain C3-7 alkylene group which may be substituted with is more preferable.

In the present invention

As a single bond or a double bond, it is preferable.

In the present invention

as,
(1) = CH- (1~3 amino ^R C2-6 alkylene group which may linear substituted with ^{L1a) -, (2) -} ( substituted with 1-3 ^{R L1a} C3~7 alkylene group optionally linear) -, or (3) - (1-2 C1~3 alkylene group which may straight optionally substituted with ^{R L1a)} -O- (1-2 C1~3 alkylene group optionally straight optionally substituted with R ^L1a) - ((1) in ~ (3) ^{R L1a} is the same as defined above) are preferred,
(1) = CH- (1-3 C2~6 alkylene group which may straight optionally substituted with ^{R L1a)} -, or (2) - (optionally substituted with 1 to 3 ^{R L1a} C3~7 alkylene group which may linear) - ((1) in ~ (2) ^{R L1a} is the same as defined above) are more preferable,
(1) = CH- (straight-chain C3 alkylene group which may be substituted with ^{1 to 3 RL1a)-or} (2)-(may be substituted with ^{1 to 3 RL1a).} A linear C4 alkylene group)-(in (1) to (2), ^RL1a has the same meaning as described above) is more preferable.

In the present invention, as ^RL1a , a hydroxyl group, a halogen atom or an oxo group is preferable, and a hydroxyl group is more preferable.

In the present invention, the R ^3, a hydrogen atom is preferable.

In the present invention, the CycA is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5-10 membered monocyclic or bicyclic heterocycle, preferably benzene or a 5-6 membered monocyclic ring. Aromatic heterocycles are even more preferred.

In the present invention, CycA is preferably benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline, more preferably benzene, isoindoline or tetrahydroquinoline, and even more preferably benzene.

In the present invention, as R ⁴ , a halogen atom, a C1-4 alkyl group or a C1-4 haloalkyl group is preferable, and a halogen atom, a methyl group or a trihalomethyl group is more preferable.

In the present invention, as L ³ , -NR ^201- S (O) _2- or -CR ²⁰⁴ (OH) is preferable.

In the present invention, as L ² , -NR ^201- S (O) _2- or -CR ²⁰⁴ (OH) -CH _2- is preferable.

In the present invention, R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ , and R ²⁰⁵ are hydrogen atoms, C1 to 4 alkyl groups, C1 to 4 alkyl groups substituted with hydroxyl groups, and C3 to 6 monocyclic carbons, respectively. A C1 to 4 alkyl group substituted with a ring or a C1 to 4 alkyl group substituted with a 3- to 6-membered monocyclic heterocycle is preferable, and a hydrogen atom is more preferable. Of these, as the C1 to 4 alkyl group substituted with the C3 to 6 monocyclic carbocycle, a C1 to 4 alkyl group substituted with cyclopropane or benzene is preferable, and a 3- to 6-membered monocyclic heterocycle is used. As the substituted C1-4 alkyl group, a C1-4 alkyl group substituted with oxetane, tetrahydrofuran, or tetrahydropyran is preferable.

In the present invention, as R ³¹ , a bond or a C1 to 3 alkylene group is preferable, and a bond is more preferable.

In the present invention, as R ³² , a bond or a C1 to 3 alkylene group is preferable, and a C1 to 3 alkylene group is more preferable.

In the present invention, the CycB is preferably (1) a C5-6 monocyclic carbocycle or (2) a 5-6 membered monocyclic heterocycle, preferably benzene or a 5-6 membered monocyclic aromatic heterocycle. Is even more preferable.

In the present invention, as CycB, cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran are preferable, and benzene is more preferable.

In the present invention, the ^{R 5,} a halogen atom, C1 -4 alkyl group, preferably a C1 -4 haloalkyl group or C1 -4 alkoxy group, halogen atom, C1 -4 alkyl group, a trihalomethyl group or a C1 -4 alkoxy group Is more preferable.

In the present invention, r and t are preferably integers of 0 to 3, and more preferably integers of 0 to 2.

In the present invention, it is a partial structure in the general formula (I).

[In the formula, all symbols have the same meaning as above. ] As the structure

Is preferable

Is more preferable.

In the present invention, the formula which is a partial structure in the general formula (I).

[In the formula, all symbols have the same meaning as above. ]as,

[In the formula, all symbols have the same meaning as above. ] Is preferable.

In the present invention, the formula which is a partial structure in the general formula (I).

[In the formula, all symbols have the same meaning as above. ]as,

[In the formula, all symbols have the same meaning as above. ] Is preferable.

In the present invention, as an aspect of the general formula (I), the general formula (Ii)

[In the formula, L1 ^-i is (1) a ^{linear C2-4 alkylene group that may be substituted with 1-3 R L1a} , or (2) -O- (1-2 R). ^It represents a linear C1 to 3 alkylene group)-which may be substituted with L1a, and other symbols have the same meanings as described above. ] Can be mentioned.

In the present invention, as an aspect of the general formula (Ii), the general formula (Ii)

^{Wherein, L 1-ii} represents 1-3 ^R C2-4 alkylene group which may linear be substituted by ^L1a, the other symbols have the same meanings as described above. ],

General formula (I-iii)

^{[Wherein, L 1-iii} is (1) 1-3 C2~4 alkylene group which may straight optionally substituted with ^{R L1a} or (2) -O- (1 to 2 amino ^{R L1a,} It represents a linear C1 to 3 alkylene group) − which may be substituted with, and other symbols have the same meanings as described above. ],or

General formula (I-iv)

^{Wherein, L 1-iv} represents 1-3 ^R C2-4 alkylene group which may linear be substituted by ^L1a, the other symbols have the same meanings as described above. ] Can be mentioned.

As an embodiment of the compound represented by the general formula (Ii), (I-ii), (I-iii) or (I-iv) or a salt thereof,
(1) R ¹¹ is a C2-4 alkylene group,
(2) X is an oxygen atom,
(3) ^RL1a is a hydroxyl group,
(4) CycA is (i) C5-6 monocyclic carbocycle, or 5-10 member monocyclic or bicyclic heterocycle, (ii) benzene or 5-6 member monocyclic aromatic heterocycle. , (Iii) C5-6 monocyclic carbocycles, or (iv) benzene, cyclohexane, pyridine, thiazole, isoindolin or tetrahydroquinoline,
(5) CycB is (i) C5-6 monocyclic carbocycle or 5-6 member monocyclic heterocycle, (ii) benzene or 5-6 member monocyclic aromatic heterocycle, (iii). C5-6 monocyclic carbocycles, or (iv) cyclopentane, benzene, cyclohexane, thiophenes, pyridines or benzofurans,
(6) ^{L 2} is ^-NR 201 -S _{(O) 2} - or _{^{-CR 204 (OH) -CH 2 -}} , or ^{(7) R 11, X,} R L1a, CycA, CycB and ^{L 2} other than the symbols The aforementioned groups (eg, "preferable", "more preferred" or "more preferred" groups),
(8) Examples thereof include a compound or a salt thereof which is a combination of two or more of the definitions described in the above (1) to (7).

In the present invention, the compound represented by the general formulas (Ii), (I-ii), (I-iii) or (I-iv) or a salt thereof is preferably used.
(1) A compound or a salt thereof in which X is an oxygen atom and L ² is −NR ²⁰¹ −S (O) _2- or −CR ²⁰⁴ (OH) −CH _2-.
(2) X is an oxygen atom, L ² is −NR ²⁰¹ −S (O) _2- or −CR ²⁰⁴ (OH) −CH _2- , and CycA and CycB are C5-6 monocyclic carbon rings. A compound or a salt thereof,
(3) R ¹¹ is a C2-4 alkylene group, X is an oxygen atom, L ² is -NR ^201- S (O) _2- or -CR ²⁰⁴ (OH) -CH _2- , and CycA and CycB is C5~6 compound or a salt thereof is monocyclic carbocyclic or (4) X is an oxygen atom, ^{a R L1a} is hydroxyl, ^{L 2} is ^-NR 201 -S _{(O) 2} - or - CR ²⁰⁴ (OH) -CH _2- , and a compound or a salt thereof in which CycA and CycB are C5-6 monocyclic carbocycles.

In the present invention, as another aspect of the general formula (I), the general formula (I-1)

[In the formula, all symbols have the same meaning as above. ] Can be mentioned.
In the present invention, the general formula (I-1) is the general formula (I-1-A).

[In the formula, L ^1-2 represents a linear C2-3 alkylene group, and other symbols have the same meanings as described above. ],

General formula (I-1-B)

[In the formula, all symbols have the same meaning as above. ],

General formula (I-1-C)

[In the formula, all symbols have the same meaning as above. ],

Or general formula (I-1-D)

[In the formula, all symbols have the same meaning as above. ] Is preferable.

As an embodiment of the compound represented by the general formula (I-1-A), (I-1-B), (I-1-C) or (I-1-D) or a salt thereof,
(1) X is an oxygen atom,
(2) CycA ¹ is benzene, cyclohexane, pyridine, thiazole, isoindoline or tetrahydroquinoline,
(3) CycB ¹ is cyclopentane, benzene, cyclohexane, thiophene, pyridine or benzofuran,
(4) ^{Symbols other than X, CycA 1} and CycB ¹ are the above-mentioned groups (for example, groups designated as "preferable", "more preferable" or "more preferable").
(5) Examples thereof include a compound or a salt thereof which is a combination of two or more of the definitions described in the above (1) to (4).

[Isomer]
In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Indicates that it is connected to the other side of the paper (that is, α arrangement).

Indicates that it is connected to the front side of the paper (that is, β arrangement).

Indicates that it is a mixture of any ratio of α-configuration and β-configuration.

In the present invention, isomers include all of them unless otherwise specified. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene, alkylidene, alkenylidene include straight and branched chains. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings, fused rings, isomers due to the presence of asymmetric carbons (R, S isomers, α, β arrangements, enantiomers, diastereomers) , Optically active substances with racemic properties (D, L, d, l), polar bodies by chromatograph separation (high polar and low polar), equilibrium compounds, rotational isomers, mixtures of any proportions thereof, All racemic mixtures are included in the present invention.

Further, the optically active compound in the present invention may contain not only 100% pure compounds but also less than 50% other optically active compounds.

In the present invention, all references relating to the compounds of the present invention are represented by the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvent product thereof, or a co-crystal thereof, or a general formula (I). Includes N-oxides of salts of compounds, solvates thereof, or co-crystals thereof.

The compound represented by the general formula (I) is converted into a corresponding salt by a known method. The salt is preferably water-soluble. Further, the salt is preferably a pharmaceutically acceptable salt. Such salts include alkali metal (lithium, potassium, sodium, etc.) salts, alkaline earth metals (calcium, magnesium, etc.) salts, other metal (silver, zinc, etc.) salts, ammonium salts, and pharmaceuticals. Acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazin, monoethanolamine, diethanolamine, tris ( Salts and acids of (hydroxymethyl) aminomethane, N-benzyl-2-phenethylamine, deanol, 2- (diethylamino) ethanol, 1- (2-hydroxyethyl) pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc.) Additive salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfates, phosphates, nitrates, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, etc.) Salts, oxalates, fumarates, maleates, benzoates, citrates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, isethionates, napadisylates, Glucronate, gluconate, etc.), etc.) and the like.

The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof may exist in an unsolvated form, or may be in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. May exist in. The solvate is preferably low toxicity and water soluble, more preferably a hydrate. The compound represented by the general formula (I) and a salt thereof can be converted into a solvate by a known method.

The N-oxide compound of the compound represented by the general formula (I) represents a compound in which the nitrogen atom of the compound represented by the general formula (I) is oxidized. Further, the N-oxide compound of the compound represented by the general formula (I) may be further the above-mentioned alkali (earth) metal salt, ammonium salt, organic amine salt and acid adduct salt.

The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof may be present in the form of co-crystals formed with a suitable co-crystal forming agent. As the co-crystal, a pharmaceutically acceptable one formed with a pharmaceutically acceptable co-crystal forming agent is preferable. A co-crystal is typically defined as a crystal formed by two or more different intermolecular interactions. Further, the co-crystal may be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal forming agents include organic acids (malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, isonicotinic acid, etc.), Organic amines (imidazole, diethanolamine, triethanolamine, tris (hydroxymethyl) aminomethane, N-benzyl--phenethylamine, deanol, 2- (diethylamino) ethanol, 1- (2-hydroxyethyl) pyrrolidine, 4- (2-) (Hydroxyethyl) morpholin, N-methyl-D-glucamine, glycine, histidine, proline, etc.), other organic compounds (caffeine, saccharin, etc.) and the like can be mentioned.

The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into the compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in vivo. Examples of the prodrug of the compound represented by the general formula (I) include, for example, when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, , The amino group of the compound represented by the general formula (I) is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranyl. (Pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compound, etc.); When the compound represented by the general formula (I) has a hydroxyl group, the hydroxyl group is acylated or alkylated. Compounds, phosphorylated, and boried compounds (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonyl. (I); when the compound represented by the general formula (I) has a carboxy group, the compound in which the carboxy group is esterified or amidated (for example, the carboxy group of the compound represented by the general formula (I)). Ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1) , 3-Dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamided compounds, etc.) and the like. These compounds can be produced by methods known per se. Further, the prodrug of the compound represented by the general formula (I) may be a solvate. Further, the prodrug of the compound represented by the general formula (I) is prepared under the physiological conditions as described in Hirokawa Shoten 1990, "Drug Development", Vol. 7, "Molecular Design", pp. 163-198. It may be changed to the compound represented by (I). Further, the compounds represented by the general formula (I) are isotopes (for example, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³⁵ S, ^It may be labeled with 18 F, ³⁶ Cl, ¹²³ I, ¹²⁵ I, etc.).

[Method for producing the compound of the present invention]
The compound of the present invention is a known method, for example, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999), or the method shown in Examples. Etc. can be appropriately improved and used in combination to produce the product.

Among the compounds represented by the general formula (I), the general formula (IA)

^{(Wherein, L 1M} (1) 1-4 ^R C2-6 alkylene group which may linear be substituted by ^L1a, optionally substituted by (2) 1-4 ^{R L1a} C2~6 alkenylene group optionally linear, (3) 1-4 C2~6 alkynylene group which may straight optionally substituted with ^{R L1a} or (4), (substituted with one to two ^{R L1a} is represents a C1 -3 alkylene group) -O- good straight even though (1-2 ^R C1 -3 alkylene group which may linear substituted with ^L1a), and other symbols are as above The compound represented by (having the same meaning) can be produced by the method shown in the following reaction step formula 1.

(In the formula, H represents a halogen atom, and other symbols have the same meanings as described above.)
In Reaction Step Formula 1, Reaction 1-1 is a nucleophilic addition using the compound represented by the general formula (A-1) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. It can be carried out by subjecting it to a reaction. This nucleophilic addition reaction is known, for example, an organic solvent (hexane, heptane, octane, benzene, toluene, tetrahydrofuran (hereinafter abbreviated as THF), dioxane, dimethoxyethane, diethyl ether, or a mixed solvent of two or more thereof, etc. ) Medium or solvent-free, at a temperature of 0-120 ° C. It can also be carried out in the presence of a catalyst for the purpose of promoting the reaction. Examples of the catalyst include formic acid, acetic acid, benzoic acid, 4-dimethylaminobenzoic acid, Schwartz's reagent (CAS Registry Number: 37342-97-5) and the like.

In the reaction step formula 1, the reaction 1-2 can be carried out by subjecting the compound represented by the general formula (A-2) and the compound represented by the general formula (A-3) to the Suzuki coupling reaction. can. This Suzuki coupling reaction is known, for example, organic solvents (toluene, benzene, N, N-dimethylformamide (hereinafter abbreviated as DMF), THF, methanol, ethanol, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide). Etc.), or in water, or a mixed solvent of two or more of them, palladium catalyst (tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ), dichlorobis (triphenylphosphine) palladium (Cl ₂ Pd (PPh ₃ )). ₂ ), Palladium acetate (Pd (OAc) ₂ ), bis (tri-tert-butylphosphine) palladium (0) (Pd (tBu3P) 2), etc.) in the presence of bases (sodium hydroxide, potassium hydroxide, triethylamine) , Sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, tallium carbonate, tripotassium phosphate, cesium fluoride, palladium hydroxide, tetrabutylammonium fluoride, etc.) ..

Further, by subjecting the compound represented by the general formula (IA) to a reduction reaction, the general formula (IB) is obtained.

(In the formula, all symbols have the same meanings as described above.) The compound represented by the above can be produced. This reduction reaction is known and can be carried out by the following method. For example, (1) a reduction reaction using a metal, (2) a diimide reduction reaction and the like can be mentioned. (1) The reduction reaction using a metal includes, for example, an organic solvent (for example, THF, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, DMF, ethyl acetate, acetic acid, water, etc. Or in the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, lane nickel, ruthenium chloride, etc.) in a mixed solvent of two or more of them, an acid (palladium-carbon, palladium black, palladium, palladium hydroxide, etc.) In the presence or absence of hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid (hereinafter abbreviated as TFA), formic acid, etc. It is carried out at 0 to 200 ° C. under a hydrogen atmosphere under normal pressure or pressure. (2) The diimide reduction reaction is carried out in, for example, an organic solvent (toluene, benzene, DMF, THF, acetonitrile, dimethoxyethane, acetone, dioxane, dimethylacetamide, methanol, ethanol or a mixed solvent of two or more thereof, etc.) and a hydrazine compound. 0 to 120 ° C. in the presence or absence of (hydrazine, hydrazine monohydrate, tosylhydrazine, etc.) and bases (sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, etc.) Can be done with.

Among the compounds represented by the general formula (I), the general formula (IC)

The compound represented by (the symbols in the formula have the same meanings as described above) can be produced by the method shown in the following reaction step formula 2.

(In the formula, all symbols have the same meaning as above.)
In the reaction step formula 2, the reaction 2-1 can be carried out by subjecting the compound represented by the general formula (A-1) and the compound represented by the general formula (A-3) to the Sonogashira reaction. This sorghum reaction is known, for example, organic solvents (ethyl acetate, isopropyl acetate, benzene, toluene, xylene, heptane, cyclohexane, THF, dioxane, dimethoxyethane, ethanol, 2-propanol, polyethylene glycol, dimethyl sulfoxide, DMF. , N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, methylene chloride, chloroform, acetone, acetonitrile), or water, or a mixed solvent of two or more of them, or under solvent-free conditions. Triethylamine, propylamine, diisopropylamine, diisopropylethylamine, dibutylamine, tributylamine, pyrrolidine, piperidine, N-methylpiperidin, 1,4-diazabicyclo [2.2.2] octane, pyridine, sodium hydroxide, sodium hydrogencarbonate, In the presence of sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, potassium fluoride, etc.), the solvent (palladium catalyst (tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ )), dichlorobis (triphenyl) Phosphine) palladium (Cl2Pd (PPh ₃ ) ₂ ), palladium acetate (Pd (OAc) ₂ ), bis (tri-tert-butylphosphine) palladium (0) (Pd (tBu ₃ P) ₂ ), etc.), or with them. Presence of interphase transfer catalyst (eg, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium acetate, etc.) in the presence of a copper catalyst (mixture with copper (I) iodide, etc.) It is carried out by reacting in the presence or absence of room temperature to 120 ° C.

Of the compounds represented by the general formula (A-3) in the reaction process formulas 1 and 2, the general formula (A-3-1)

(In the formula, all symbols have the same meanings as described above.) The compound represented by the above can be produced by the method shown in the following reaction step formula 3.

(In the formula, all symbols have the same meaning as above.)

In the reaction step formula 3, the reaction 3-1 is carried out by subjecting the compound represented by the general formula (A-3-1a) and the compound represented by the general formula (A-3-1b) to a sulfonamide reaction. Can be done. This sulfonamide reaction is known, for example, organic solvents (ethyl acetate, isopropyl acetate, benzene, toluene, xylene, heptane, cyclohexane, THF, dioxane, dimethoxyethane, ethanol, 2-propanol, dimethyl sulfoxide, DMF, N. , N-Dimethylacetamide, N-methyl-2-pyrrolidinone, methylene chloride, chloroform, acetone, acetonitrile, or a mixed solvent of two or more of them) or under solvent-free conditions (diisopropylethylamine, pyridine, triethylamine, etc.) In the presence or absence of dimethylaniline, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, etc.), in the presence or absence of a solvent (4-dimethylaminopyridine, etc.), It is carried out by reacting at 0 to 120 ° C.

In the reaction step formula 3, in the reaction 3-2, the compound represented by the general formula (A-3-1c) and the compound represented by the general formula (A-3-1d) are subjected to an alkylation reaction, or the general formula is used. It can be carried out by subjecting the compound represented by (A-3-1c) and the compound represented by the general formula (A-3-1e) to the Mitsunobu reaction. This alkylation reaction is known and is based in, for example, in an organic solvent (such as DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, acetonitrile, water, or a mixed solvent of two or more thereof). (Sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl)) It is carried out by reacting at 0 to 100 ° C. in the presence of (amide, etc.). This Mitsunobu reaction is known, for example, in an organic solvent (dimethane, diethyl ether, THF, acetonitrile, benzene, toluene, etc.), an azo compound (diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-(azodi). In the presence of carbonyl) dipiperidin, 1,1'-azobis (N, N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.) at 0-80 ° C. It is done by reacting.

Of the compounds represented by the general formula (A-3) in the reaction process formulas 1 and 2, the general formula (A-3-2)

(In the formula, all the symbols have the same meanings as described above.) The compound represented by the above can be produced by the method shown in the following reaction step formula 4.

(In the formula, all symbols have the same meaning as above.)

In the reaction step formula 4, the reaction 4-1 contains the compound represented by the general formula (A-3-2a) in an organic solvent (for example, THF, dimethoxyethane, toluene, dichloromethane, diethyl ether, dioxane, methanol, etc.). It is carried out by reacting in the presence or absence of cerium chloride with a reducing agent (for example, sodium borohydride, zinc borohydride, etc.) at −20 to 50 ° C. When only one of the three steric isomers is selectively produced, an asymmetric reducing agent (for example, chlorodiisopynocanphenylborane, etc.) or a combination of an asymmetric auxiliary and a reducing agent ((R)-) 2-Methyl-CBS-oxazaborolidine and boron hydride-THF complex or borane dimethyl sulfide complex, (S)-(-)-binaphthol and lithium aluminum hydride, etc.) at a temperature of -100 to 50 ° C. It is done in.

When a protecting group is present in the compound represented by each of the reaction step formulas 1, the reaction step formula 2, the reaction step formula 3 or the reaction step formula 4, a deprotection reaction can be carried out if necessary. The deprotection reaction of this protecting group is known and can be carried out by the following method. For example, (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenation, (4) deprotection reaction of silyl group, (5) metal. Examples thereof include a deprotection reaction used, and (6) a deprotection reaction using a metal complex.

To explain these methods in detail,
(1) The deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (for example, methanol, THF, dioxane, etc.), an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), Alkaline earth metal hydroxide (eg, barium hydroxide, calcium hydroxide, etc.) or carbonate (eg, sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof is used at 0 to 40 ° C. Is done.
(2) The deprotection reaction under acid conditions is carried out in, for example, an organic acid (for example, acetic acid, trifluoroacetic acid) in an organic solvent (for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.). , Methanesulfonic acid, p-tosylic acid, etc.), or inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (eg, hydrogen bromide / acetic acid, etc.) in the presence of 2,2,2-trifluoroethanol. It is carried out at 0 to 100 ° C. under or in the absence.
(3) The deprotection reaction by hydrogenation is, for example, a solvent (for example, ether type (for example, THF, dioxane, dimethoxyethane, diethyl ether, etc.)), an alcohol type (for example, methanol, ethanol, etc.), a benzene type (for example, for example, methanol, ethanol, etc.). Benzene, toluene, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), amides (eg, DMF, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc. ), In the presence of a solvent (eg, palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, lane nickel, etc.), in a hydrogen atmosphere under normal pressure or pressure, or in the presence of ammonium formate, at 0 to 200 ° C. It is done.
(4) The deprotection reaction of the silyl group is carried out at 0 to 40 ° C. using, for example, tetrabutylammonium fluoride in an organic solvent miscible with water (for example, THF, acetonitrile, etc.). Also, for example, organic acids (eg, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (eg, hydrogen bromide / acetic acid, etc.) ), The temperature is -10 to 100 ° C.
(5) In the deprotection reaction using a metal, for example, the presence of powdered zinc in an acidic solvent (for example, acetic acid, a buffer solution having a pH of 4.2 to 7.2 or a mixture thereof and an organic solvent such as THF). Below, it is carried out at 0 to 40 ° C. while applying ultrasonic waves if necessary.
(6) The deprotection reaction using a metal complex is carried out in, for example, an organic solvent (for example, dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof, and a trap reagent (for example, hydrogenation). Tributyltin, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (eg, acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or organic acid salts (eg, sodium 2-ethylhexanoate, 2-ethyl) In the presence or absence of a phosphine reagent (eg, triphenylphosphine, etc.) in the presence of potassium hexanoate, etc.), a metal complex (eg, tetrakistriphenylphosphine palladium (0), bis dichloride (triphenylphosphine)). It is carried out at 0 to 40 ° C. using palladium (II), palladium (II) acetate, tris (triphenylphosphine) rhodium (I), etc.).

In addition to the above, the deprotection reaction can be carried out by, for example, the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
Examples of the hydroxyl group protective group include a methyl group, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, a 2-tetrahydropyranyl (THP) group and a trimethylsilyl group. (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, benzyl (Bn) group, Examples thereof include a p-methoxybenzyl group, an allyloxycarbonyl (Allloc) group, a 2,2,2-trichloroethoxycarbonyl (Troc) group and the like.

Examples of the amino group protecting group include a benzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl (Alloc) group, a 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc) group, and a trifluoroacetyl group. , 9-Fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2- (trimethylsilyl) ethoxymethyl (SEM) group and the like.
The protecting group for the hydroxyl group and the amino group is not particularly limited as long as it is a group that can be easily and selectively eliminated in addition to the above. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.

In each reaction in the present specification, the compounds used as starting materials are represented by the general formulas (A-1), (A-3), (A-3-1a) and (A-3-1b). The compound is known or can be easily produced by a known method.

In each reaction herein, the reaction involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.

In each reaction in the present specification, a solid-phase supporting reagent supported on a high-molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

In each reaction herein, the reaction product is prepared by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography with silica gel or magnesium silicate, thin layer chromatography, ion exchange resins. It can be purified by a scavenger resin or a method such as column chromatography or washing or recrystallization. Purification may be performed on a reaction-by-reaction basis or after the completion of several reactions.

[toxicity]
The toxicity of the compound of the present invention is sufficiently low, and it can be safely used as a pharmaceutical product.

[Application to pharmaceutical products]
The compounds of the present invention have neuroprotective and / or repairing effects.
In one embodiment, the compounds of the present invention have a long-lasting neuroprotective and / or repairing effect.
Therefore, the compound of the present invention is useful, for example, in the treatment of diseases associated with neuropathy.

In the present invention, as an aspect having a neuroprotective and / or repairing action, neuroprotective and / or repair via glial cells (for example, microglia, astrocytes, oligodendrocytes, ependymal cells, Schwann cells, satellite cells, etc.) The action is mentioned. Aspects of glial cell-mediated neuroprotective and / or repair action include Schwann cell differentiation promoting action (including Schwann cell myelination promoting action).
In the present invention, neuropathy includes peripheral neuropathy and central neuropathy. Diseases associated with peripheral neuropathy include, for example, diabetic neuropathy, metabolic peripheral neuropathy associated with urinary toxicosis, peripheral neuropathy associated with vitamin B deficiency, diphtheria, botulinum food poisoning, and infectious diseases such as herpesvirus (herpes zoster). Peripheral neuropathy associated with, anticonvulsant phenitoin, antibacterial agents (chloramphenicol, nitrofurantin, sulfonamides, etc.), chemotherapeutic agents (taxan: paclitaxel, docetaxel, etc., platinum preparations: oxaliplatin, cisplatin) , Carboplatin, Nedaaplatin, etc., Vinca alkaloids: binbrastin, bincristin, bindesin, etc.), drug-induced peripheral neuropathy associated with administration of sedatives (barbital, hexobarbital, etc.), chronic inflammatory demyelinating polyneuritis, Giran Valley Immunity such as syndromes, strangulation neuropathy (eg, carpal canal syndrome, thoracic exit syndrome, elbow canal syndrome, pear muscle syndrome, ankle canal syndrome, peroneal nerve strangulation disorder, etc.) Peripheral neuropathy, periarteritis nodule, allergic vasculitis, peripheral neuropathy associated with allergic diseases such as systemic erythematosus, heavy metals such as lead, mercury, arsenic and tarium, organic solvents such as thinner, organic phosphorus pesticides , Toxic substances such as triolsocrecil phosphate (TOCP), addictive peripheral neuropathy associated with alcohol intake, peripheral neuropathy due to cancer compression of nerves, hereditary diseases (eg, hypothyroidism, kidneys) Peripheral neuropathy associated with insufficiency, Sharko Marie Tooth's disease, Leftham's disease, porphyrinosis, Fabry's disease, hereditary pressure vulnerability neuropathy, etc.).

Diseases associated with central neuropathy include, for example, Alzheimer's disease, Parkinson's disease, Levy body dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Huntington's disease, dystonia, prion. Disease, multisystem atrophy, spinal cerebral degeneration, muscular atrophic lateral cord sclerosis, primary lateral cord sclerosis, bulbous muscular atrophy, spinal muscular atrophy, spastic antiparalysis, spinal cavities, multiple Infectious neuropathy such as sclerosis, optic neuromyelitis, concentric sclerosis, acute diffuse encephalomyelitis, inflammatory diffuse sclerosis, subacute sclerosis total encephalitis, progressive multifocal leukoencephalopathy, hypoxic encephalopathy and Intoxication / metabolic neuropathy such as pons-central medullary sheath destruction, and vascular neuropathy such as Binswanger's disease can be mentioned.

In the present invention, as aspects of neuropathy, chronic inflammatory demyelinating polyneuritis, Gillan Valley syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, chemotherapy Peripheral neuropathy associated with drug (including anticancer drug) administration, or peripheral neuropathy associated with Charcot-Marie-Tooth disease.

In the present invention, one embodiment of prevention and / or treatment of peripheral neuropathy includes prevention and / or treatment of subjective symptoms (numbness, pain) or dyskinesia associated with peripheral neuropathy, and another embodiment. Includes prevention and / or treatment of pain associated with peripheral neuropathy.

The combination drug of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in the form of separate preparations. When administered as these separate formulations, simultaneous administration and staggered administration are included. Further, for administration with a time lag, the compound of the present invention may be administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. Each administration method may be the same or different.

The disease that exerts a prophylactic and / or therapeutic effect by the above-mentioned combination drug is not particularly limited as long as it is a disease that complements and / or enhances the prophylactic and / or therapeutic effect of the compound of the present invention.

Other drugs for complementing and / or enhancing the prophylactic and / or therapeutic effect of the compounds of the present invention on diseases associated with neurological disorders include, for example, aldose reductase inhibitors, vitamins, and brain protectants. Examples of the aldose reductase inhibitor include epalrestat. Examples of vitamin preparations include mecobalamin. Examples of the brain protective drug include edaravone.

In addition, the combination drugs to be combined with the compound of the present invention include not only those found up to now but also those found in the future.

The compounds of the present invention are usually formulated as suitable pharmaceutical compositions with a pharmaceutically acceptable carrier and then administered systemically or topically, orally or parenterally. Oral preparations include, for example, liquid preparations for internal use (eg, elixirs, syrups, pharmaceutically acceptable liquids, capsules, emulsions), solid preparations for internal use (eg, tablets (sublingual tablets, intraoral tablets)). (Including disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules), powders, granules, troches, etc. Examples of parenteral preparations include liquid preparations (for example, intravitreal injections, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, eye drops, etc.) and eye drops (eg, aqueous drops). Eye drops (aqueous eye drops, aqueous suspended eye drops, viscous eye drops, solubilized eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspended eye drops, etc.)), external preparations (for example, , Ointments (eye ointments, etc.)), eye drops, etc. These preparations may be release control agents such as immediate release preparations and sustained release preparations. These preparations can be produced by a known method, for example, the method described in the Japanese Pharmacopoeia.

Oral solutions are produced, for example, by dissolving, suspending or emulsifying the active ingredient in commonly used diluents (eg purified water, ethanol or a mixture thereof). Further, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance agent, a preservative, a buffering agent and the like.

For the solid preparation for internal use as an oral preparation, for example, the active ingredient is an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, aluminen metasilicate). Mix with a disintegrant (eg, calcium fibrous glycolate, etc.), a lubricant (eg, magnesium stearate, etc.), a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, etc.), etc. It is formulated according to. Further, if necessary, it may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or may be coated with two or more layers.

External preparations as parenteral preparations are manufactured by known methods or commonly used formulations. For example, an ointment is produced by triturating or melting an active ingredient as a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes. (For example, beeswax, whale wax, selecin, etc.), surfactants (for example, polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (for example, cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicon oil (for example, for example. Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic vaseline, white vaseline, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oil (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.) , Ester oil, olive oil, sesame oil, terepine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalane, etc.), water, absorption enhancer, anti-fog agent, alone or a mixture of two or more. Used for Further, it may contain a moisturizer, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like.

Injections as parenteral preparations include solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent for use. Injectables are used, for example, by dissolving, suspending or emulsifying the active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and the like, and combinations thereof are used. Further, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. May be good. These are sterilized in the final step or manufactured by aseptic technique. It is also possible to produce a sterile solid preparation, for example, a lyophilized product, which is sterilized or dissolved in sterile distilled water for injection or other solvent before use.

To use the compound of the present invention or a combination drug of the compound of the present invention and another drug for the above purpose, it is usually administered systemically or topically, orally or parenterally. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1 ng to 1000 mg per adult. Or, per adult, it is orally administered once to several times a day in the range of 0.1 ng to 10 mg, or continuously administered intravenously in the range of 1 hour to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, an amount smaller than the above dose may be sufficient, or administration beyond the range may be necessary.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

The location of the separation by chromatography and the solvent in parentheses shown on the TLC indicate the elution solvent or developing solvent used, and the ratio represents the volume ratio.
The conditions used in the LC / MS analysis in the following examples are shown below.
Column: YMC Triart C18, 2.0 mm × 30 mm, 1.9 μm; Flow rate: 1.0 mL / min; Temperature: 30 ° C.; Mobile phase A: 0.1% TFA aqueous solution; Mobile phase B: 0.1% TFA acetonitrile Solution: Gradient (state the ratio of mobile phase A: mobile phase B): 0 to 0.10 minutes (95: 5), 0.10 to 1.20 minutes (95: 5 to 5:95), 1.20 Minutes to 1.50 minutes (5:95).
The number in parentheses shown in the NMR section indicates the solvent used for the measurement.
The compound names used herein are generally ACD / Name® from Advanced Chemical Development, a computer program that names according to the IUPAC rules, or according to the IUPAC nomenclature. It is named.

Example 1: Sulfuric acid (0.26 mL) is added to a solution of isopropyl 3- (2-hydroxyphenyl) propanoate 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL), and the reaction mixture is mixed at room temperature for 2 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (73.2 g) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35.

Example 2: Isopropyl 3- (2- (2- (1,3-dioxane-2-yl) ethoxy) phenyl) propanoate The compound (2.00 g) and 2- (2-bromoethyl)-prepared in Example 1. Potassium phosphate (2.85 g) was added to a solution of 1,3-dioxane (2.43 g) in DMF (4 mL), and the reaction mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 4: 1) to give the title compound (2.73 g) having the following physical characteristics.
TLC: Rf0.57 (hexane: ethyl acetate = 2: 1).

Example 3: Isopropyl 3- (2- (3-oxopropoxy) phenyl) propanoate Cool a solution of the compound (500 mg) and lutidine (0.40 mL) prepared in Example 2 in dichloromethane (1.5 mL) to -15 ° C. Then, trimethylsilyltrifluoromethanesulfonate (0.42 mL) was added. The reaction mixture was stirred at 0 ° C. for 2 hours. Ice (10 g) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 15 minutes. Water and ethyl acetate were added, and the mixture was stirred at 0 ° C. for 20 hours, the reaction mixture was poured into 1M hydrochloric acid and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (443 mg) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 1.20, 2.50-2.55, 2.93-2.96, 4.33, 4.98, 6.85-6.92, 7.14-7.19, 9.90.

Example 4: A solution of isopropyl 3-(2-((3-hydroxy-5- (trimethylsilyl) penta-4-in-1-yl) oxy) phenyl) propanoate trimethylsilylacetylene (5.0 mL) in THF (70 mL). The mixture was cooled to −70 ° C., n-butyllithium (1.6 M hexane solution, 20 mL) was added, and the reaction mixture was stirred at −70 ° C. for 30 minutes. A solution of the compound (7.15 g) prepared in Example 3 in THF (10 mL) was added dropwise, and the reaction mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 7: 3) to give the title compound (1.8 g) having the following physical property values.
^{1 1} H-NMR (CDCl ₃ ): δ 0.17, 1.19, 2.22-2.33, 2.56, 2.87-2.98, 4.09-4.23, 4.70, 3.60-4.93-5.03, 6.86-6.91, 7.14-7.18.

Example 5: Isopropyl 3- (2-((3-hydroxypenta-4-in-1-yl) oxy) phenyl) propanoate 0 in THF (38 mL) solution of the compound (6.89 g) prepared in Example 4. After cooling to ° C., tetrabutylammonium fluoride (hereinafter abbreviated as TBAF) (1.0 M THF solution, 7.3 mL) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 1: 1) to give the title compound (5.06 g) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 1.19, 2.20-2.26, 2.43, 2.50-2.59, 2.87-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.

Example 6: Isopropyl (R) -3-(2-((3-hydroxypenta-4-in-1-yl) oxy) phenyl) propanoate Heptane (24 mL) of the compound (1.2 g) prepared in Example 5 ) Vinyl acetate (4 mL) was added to the solution. CHIRAZYME L-5 CA (trade name) (0.4 g) was added and the reaction mixture was stirred at 45 ° C. for 9 hours. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 1: 1) to give the title compound (0.54 g,> 99% ee) having the following physical characteristics. .. The obtained compound was subjected to high performance liquid chromatography (column used: Daicel Co., Ltd. CHIRALPAK-IB (4.6 mm × 250 mm), mobile phase: hexane: 2-propanol = 95: 5, flow velocity: 1 mL / min, wavelength: 254 nm, As a result of analysis at a column temperature (40 ° C.), the holding time was 10.6 minutes.
^{1 1} H-NMR (CDCl ₃ ): δ 1.19, 2.20-2.26, 2.41, 2.50-2.59, 2.90-2.96, 4.08-4.26, 4.74, 4.99, 6.86-6.91, 7.14-7.21.

Example 7: Isopropyl (R) -3-(2-((3-((trimethylsilyl) oxy) penta-4-in-1-yl) oxy) phenyl) propanoate of the compound (500 mg) prepared in Example 6. The DMF (3.4 mL) solution was cooled to 0 ° C. and chlorotrimethylsilane (0.24 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 9: 1) to give the title compound (600 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 0.17, 1.21, 2.18, 2.43, 2.54-2.59, 2.90-2.95, 4.06-4.15, 4.67, 4.99, 6.83-6.89, 7.14-7.20.

Example 8: Isopropyl (R, E) -3-(2-((5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-((trimethylsilyl)) ) Oxy) penta-4-ene-1-yl) oxy) phenyl) propanoate In a heptane (6 mL) solution of the compound (2.45 g) prepared in Example 7, 4,4,5,5-tetramethyl-1 , 3,2-Dioxaborolane (2.09 g) and 4-dimethylaminobenzoic acid (53.9 mg) were added, and the mixture was stirred at 100 ° C. for 13 hours. The reaction solution was cooled to room temperature and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 3: 1) to give the title compound (1.45 g) having the following physical characteristics.
HPLC retention time (minutes): 1.14.

Example 9: N- (3-Bromophenyl) Benzene Sulfonamide In a solution of 3-bromoaniline (1.02 g) in dichloromethane (20 mL) at 0 ° C., pyridine (0.95 mL), N, N-dimethylaminopyridine ( Hereinafter, DMAP (abbreviated as DMAP) (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, the obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) to give the title compound (1.96 g) having the following physical characteristics. rice field.
HPLC retention time (minutes): 0.98.

Example 10: Propane-2-yl 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate In Example 8. In a solution of the prepared compound (2.00 g) in THF (18 mL), the compound (1.18 g) prepared in Example 9, chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1 , 1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] palladium (II) (CAS registration number: 131584-14-5) (0.30 g) and 2M tripotassium phosphate aqueous solution (5.7 mL) was added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. TBAF (1.0 M THF solution, 6.3 mL) was added to the obtained residual THF (6 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) to give the title compound (1.41 g) having the following physical characteristics.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 1.21, 2.05-2.17, 2.21, 2.57-2.61, 2.91-2.95, 4.11-4.19, 4.62, 5.02, 6.25, 6.55, 6.72, 6.85-6.91, 6.99, 7.09-7.22, 7.41-7.45, 7.53, 7.75-7.78.

Example 11: 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid

A 1 M aqueous lithium hydroxide solution (5 mL) was added to a solution of the compound (680 mg) prepared in Example 10 in THF (5 mL) and methanol (1 mL), and the mixture was stirred at 30 ° C. for 18 hours. It was acidified by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (600 mg) having the following physical characteristics.
HPLC retention time (minutes): 0.93;
^{1 1} H-NMR (CD ₃ OD): δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45-7.50, 7.56 , 7.75-7.78.

Examples 12 (1) to (13)
By using a halide compound corresponding to the N- (3-bromophenyl) benzenesulfonamide used in Example 10 and subjecting it to the same operation as in Example 10 → Example 11, the following Examples The compound was obtained.

Example 12 (1): 3- [2-[(E, 3R) -5- (3-benzamide phenyl) -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0. 95;
^{1 1} H-NMR (CD ₃ OD): δ 2.10-2.15, 2.59-2.63, 2.93-2.97, 4.13, 4.21, 4.60, 6.39, 6.67, 6.86, 6.95, 7.16, 7.24, 7.33, 7.52-7.63, 7.81, 7.95 -7.97.

Example 12 (2): 3- [2-[(E, 3R) -5- [4- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid

HPLC retention time (minutes): 0.92;
MS (ESI, Pos.): 464 (M + H-H ₂ O) ⁺ .

Example 12 (3): 3- [2-[(E, 3R) -5- (4-benzamide phenyl) -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0. 95;
^{1 1} H-NMR (CD ₃ OD): δ 2.10-2.14, 2.58-2.63, 2.93-2.97, 4.13, 4.20, 4.58, 6.32, 6.64, 6.86, 6.95, 7.15-7.20, 7.44-7.55, 7.60, 7.67-7.71 , 7.93-7.97.

Example 12 (4): 3- [2-[(E, 3R) -5- [2- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) ): 0.94;
MS (ESI, Pos.): 464 (M + H-H ₂ O) ⁺ .

Example 12 (5): 3- [2-[(E, 3R) -5- (2-benzamide phenyl) -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0. 89;
MS (ESI, Pos.): 428 (M + H-H ₂ O) ⁺ .

Example 12 (6): 3- [2-[(E, 3R) -5- [3- (benzylamino) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) : 0.85;
^{1 1} H-NMR (CD ₃ OD): δ 2.05-2.10, 2.57-2.61, 2.92-2.95, 4.10, 4.17, 4.33, 4.52, 6.19, 6.49-6.56, 6.69-6.71, 6.85, 6.93, 7.04, 7.15-7.24 , 7.29-7.33, 7.37-7.39.

Example 12 (7): 3- [2-[(E, 3R) -3-hydroxy-5- [3- (phenylsulfamoyl) phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time ( Minutes): 0.94;
MS (ESI, Pos.): 464 (M + H-H ₂ O) ⁺ .

Example 12 (8): 3- [2-[(E, 3R) -3-hydroxy-5-[3- (phenylcarbamoyl) phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) : 0.95;
MS (ESI, Pos.): 428 (M + H-H ₂ O) ⁺ .

Example 12 (9): 3- [2-[(E, 3R) -3-hydroxy-5-[3- (1-hydroxy-2-phenylethyl) phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CD ₃ OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.62, 6.86, 6.94, 7.10-7.31.

Example 12 (10): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide methyl) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time ( Minutes): 0.93;
MS (ESI, Pos.): 478 (M + H-H ₂ O) ⁺ .

Example 12 (11): 3- [2-[(E, 3R) -5- [2- (benzenesulfonamide methyl) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time ( Minutes): 0.97;
^{1 1} H-NMR (CDCl ₃ ): δ 1.99-2.07, 2.11-2.19, 2.68-2.72, 2.95-3.08, 4.12-4.26, 4.73-4.78, 6.12, 6.59, 6.86-6.92, 7.04-7.11, 7.16-7.23, 7.33-7.38, 7.44-7.48, 7.64-7.67.

Example 12 (12): 3- [2-[(E, 3R) -5-[1- (benzenesulfonyl) -2-methylindole-4-yl] -3-hydroxypenta-4-enoxy] phenyl] Propanic acid HPLC retention time (minutes): 1.10;
MS (ESI, Pos.): 502 (M + H-H ₂ O) ⁺ .

Example 12 (13): 3- [2-[(E, 3R) -3-hydroxy-5- [3- (2-hydroxy-1-phenylpropan-2-yl) phenyl] penta-4-enoxy] Phenyl] propanoic acid HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.65-2.68, 2.94-3.14, 4.12-4.22, 4.62, 6.28, 6.64, 6.86-6.91, 7.00-7.02, 7.15-7.28, 7.44.

Examples 13 (1) to (19)
By substituting the amine compound corresponding to 3-bromoaniline used in Example 9 for the same operation as in Example 9 → Example 10 → Example 11, the following Example compound is obtained. rice field.

Example 13 (1): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -2-methylphenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid

HPLC retention time (minutes): 0.94;
^{1 1} H-NMR (CD ₃ OD): δ 1.96, 2.07-2.12, 2.56-2.60, 2.90-2.94, 4.10, 4.18, 4.57, 6.12, 6.78, 6.84-6.93, 7.04, 7.15-7.20, 7.36, 7.47-7.51 , 7.60, 7.65-7.67.

Example 13 (2): 3- [2-[(E, 3R) -5- [5- (benzenesulfonamide) -2-methylphenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.95;
^{1 1} H-NMR (CD ₃ OD): δ 2.05-2.11, 2.19, 2.56-2.60, 2.91-2.95, 4.09, 4.19, 4.56, 6.01, 6.76, 6.84-6.94, 6.99, 7.12-7.20, 7.44-7.48, 7.56 , 7.73-7.75.

Example 13 (3): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -5-methylphenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.96;
^{1 1} H-NMR (CD ₃ OD): δ 1.93-1.98, 2.12, 2.45-2.49, 2.79-2.83, 3.98, 4.05, 4.41, 6.09, 6.37, 6.69, 6.74, 6.80-6.83, 7.03-7.08, 7.34-7.38 , 7.44, 7.63-7.66.

Example 13 (4): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -4-methylphenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.94;
^{1 1} H-NMR (CD ₃ OD): δ 1.89-1.97, 1.91, 2.46-2.50, 2.81-2.84, 3.98, 4.06, 4.40, 5.98, 6.37, 6.75, 6.83, 6.90, 6.97, 7.04-7.09, 7.34-7.38 , 7.46, 7.56-7.58.

Example 13 (5): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -2-fluorophenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.94;
^{1 1} H-NMR (CD ₃ OD): δ 2.03-2.09, 2.55-2.59, 2.89-2.93, 4.09, 4.16, 4.53, 6.36, 6.63, 6.86, 6.92, 7.06, 7.15-7.19, 7.30-7.37, 7.45-7.49 , 7.57, 7.75-7.77.

Example 13 (6): 3- [2-[(E, 3R) -5- [5- (benzenesulfonamide) -2-fluorophenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.94;
^{1 1} H-NMR (CD ₃ OD): δ 1.90-2.01, 2.45-2.49, 2.79-2.83, 3.99, 4.07, 4.43, 6.17, 6.56, 6.75, 6.81-6.88, 7.03-7.09, 7.34-7.38, 7.45, 7.60 -7.63.

Example 13 (7): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -5-fluorophenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.96;
^{1 1} H-NMR (CD ₃ OD): δ 1.92-1.98, 2.44-2.48, 2.78-2.82, 3.98, 4.06, 4.42, 6.17, 6.39, 6.68, 6.70-6.82, 7.03-7.08, 7.37-7.41, 7.47, 7.68 -7.71.

Example 13 (8): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -4-fluorophenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.92;
^{1 1} H-NMR (CD ₃ OD): δ 1.95-2.00, 2.45-2.49, 2.81-2.84, 4.00, 4.07, 4.44, 6.10, 6.45, 6.75, 6.81-6.86, 7.04-7.10, 7.34-7.39, 7.47, 7.64 -7.66.
Example 13 (9): 3- [2-[(E, 3R) -5- [3- (benzenesulfone)

Do) -2- (trifluoromethyl) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CD ₃ OD): δ 1.94-2.00, 2.43-2.47, 2.78-2.82, 3.99, 4.06, 4.45, 6.08, 6.74, 6.79-6.85, 7.03-7.10, 7.32-7.43, 7.50, 7.58-7.60 ..

Example 13 (10): 3- [2-[(E, 3R) -5- [5- (benzenesulfonamide) -2- (trifluoromethyl) phenyl] -3-hydroxypenta-4-enoxy] phenyl ] Proanoic acid HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CD ₃ OD): δ 1.94-2.00, 2.43-2.47, 2.79-2.83, 3.99, 4.07, 4.47, 6.09, 6.73-6.82, 7.04-7.08, 7.27, 7.38-7.42, 7.48, 7.73-7.76 ..

Example 13 (11): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -5- (trifluoromethyl) phenyl] -3-hydroxypenta-4-enoxy] phenyl ] Proanoic acid HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CD ₃ OD): δ 1.91-2.03, 2.42-2.46, 2.79-2.83, 3.99, 4.07, 4.46, 6.25, 6.49, 6.74, 6.81, 7.03-7.07, 7.16, 7.22-7.26, 7.37-7.41 , 7.47, 7.67-7.70.

Example 13 (12): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -4- (trifluoromethyl) phenyl] -3-hydroxypenta-4-enoxy] phenyl ] Proanoic acid HPLC retention time (minutes): 0.97;
^{1 1} H-NMR (CD ₃ OD): δ 1.94-2.00, 2.46-2.50, 2.80-2.84, 4.00, 4.08, 4.46, 6.19, 6.49, 6.76, 6.84, 7.05-7.10, 7.24, 7.28, 7.39-7.52, 7.67 -7.70.

Example 13 (13): 3- [2-[(E, 3R) -5- [6- (benzenesulfonamide) pyridin-2-yl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.85;
^{1 1} H-NMR (CD ₃ OD): δ 1.92-2.00, 2.45-2.49, 2.79-2.83, 3.96-4.10, 4.47, 6.42, 6.64, 6.75, 6.79-6.83, 6.88, 7.03-7.08, 7.36-7.49, 7.85 -7.88.

Example 13 (14): 3- [2-[(E, 3R) -5- [1- (benzenesulfonyl) -2,3-dihydroindole-6-yl] -3-hydroxypenta-4-enoxy] Phenyl] propanoate HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 2.11-2.16, 2.59-2.63, 2.82-2.86, 2.94-2.98, 3.94-3.98, 4.14, 4.22, 4.60, 6.34, 6.66, 6.87, 6.96, 7.05-7.09, 7.16 -7.21, 7.48-7.52, 7.63, 7.66, 7.78-7.81.

Example 13 (15): 3- [2-[(E, 3R) -5- [1- (benzenesulfonyl) -2,3-dihydroindole-4-yl] -3-hydroxypenta-4-enoxy] Phenyl] propanoate HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 2.04-2.09, 2.51-2.55, 2.70-2.89, 3.89-3.96, 4.08, 4.14, 4.53, 6.23, 6.50, 6.83, 6.90, 7.08-7.19, 7.48-7.53, 7.63 , 7.78-7.81.

Example 13 (16): 3- [2-[(E, 3R) -5- [2- (benzenesulfonyl) -1,3-dihydroisoindole-5-yl] -3-hydroxypenta-4-enoxy ] Phenyl] Proanoic acid HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.10, 2.55-2.59, 2.89-2.93, 4.10, 4.17, 4.54, 4.60, 6.31, 6.60, 6.85, 6.92, 7.13-7.18, 7.28-7.30, 7.58-7.68 , 7.90-7.93.

Example 13 (17): 3- [2-[(E, 3R) -5- [1- (benzenesulfonyl) -3,4-dihydro-2H-quinoline-7-yl] -3-hydroxypenta-4 -Enoxy] phenyl] propanoate HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 1.59-1.66, 2.10-2.15, 2.40-2.43, 2.59-2.63, 2.93-2.97, 3.82-3.85, 4.14, 4.21, 4.59, 6.31, 6.62, 6.86, 6.94-7.01 , 7.16-7.21, 7.45-7.49, 7.59-7.63, 7.79.

Example 13 (18): 3- [2-[(E, 3R) -5- [1- (benzenesulfonyl) -3,4-dihydro-2H-quinoline-5-yl] -3-hydroxypenta-4 -Enoxy] phenyl] propanoate HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 1.50-1.57, 2.01-2.15, 2.19-2.37, 2.53-2.57, 2.88-2.92, 3.75-3.78, 4.07, 4.16, 4.56, 6.12, 6.67, 6.84, 6.90, 7.13 -7.21, 7.32, 7.45-7.49, 7.56-7.65.

Example 13 (19): 3- [2-[(E, 3R) -5- [2- (benzenesulfonyl) -3,4-dihydro-1H-isoquinoline-7-yl] -3-hydroxypenta-4 -Enoxy] phenyl] propanoate HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 2.07-2.12, 2.57-2.61, 2.87-2.95, 3.36-3.39, 4.11, 4.18, 4.25, 4.55, 6.29, 6.57, 6.85, 6.93, 7.05, 7.14-7.19, 7.23 , 7.59-7.70, 7.87-7.89.

Example 14: N- (3-Bromophenyl) -N- (oxetane-2-ylmethyl) benzenesulfonamide In a solution of the compound (313 mg) prepared in Example 9 in THF (2 mL), oxetane-2-ylmethanol ( 132 mg), triphenylphosphine (394 mg) and diethyl azodicarboxylate (40% toluene solution, 0.68 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to give the title compound (381 mg) having the following physical properties.
TLC: Rf 0.34 (Hexane: Ethyl acetate = 2: 1)

Example 15: 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (oxetane-2-ylmethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid By using the compound prepared in Example 14 instead of the N- (3-bromophenyl) benzenesulfonamide used in Example 10 and performing the same operation as in Example 10 → Example 11, the following operations are performed. A title compound having physical properties was obtained.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.10, 2.48-2.69, 2.91-2.95, 3.80, 4.00, 4.10, 4.18, 4.47-4.64, 4.83, 6.21, 6.55, 6.87, 6.94-6.96, 7.03, 7.17 -7.21, 7.27, 7.38, 7.50-7.54, 7.60-7.65.

Examples 16 (1) to (8)
The alcohol compound corresponding to the oxetane-2-ylmethanol used in Example 14 was used in place of the N- (3-bromophenyl) benzenesulfonamide used in Example 10 and the halide compound was used. The following compound of Example was obtained by subjecting the same operation as in Example 14 → Example 10 → Example 11.

Example 16 (1): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (oxetane-3-ylmethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] Propanic acid HPLC retention time (minutes): 0.94;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.04, 3.95, 4.10, 4.18, 4.36-4.40, 4.55, 4.63-4.67, 6.22, 6.55, 6.85-6.97, 7.16 -7.21, 7.29, 7.40, 7.52-7.56, 7.62-7.67.

Example 16 (2): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (oxolan-2-ylmethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] Propanic acid HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 1.72, 1.84-1.99, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.57, 3.66-3.80, 3.89, 4.10, 4.18, 4.55, 6.22, 6.56, 6.87, 6.94 -6.97, 7.05, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.64.

Example 16 (3): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (oxolan-3-ylmethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] Propanic acid HPLC retention time (minutes): 0.97;
^{1 1} H-NMR (CD ₃ OD): δ 1.74, 1.95, 2.06-2.11, 2.25, 2.57-2.61, 2.91-2.95, 3.57-3.61, 3.67-3.73, 3.87, 4.10, 4.19, 4.55, 6.23, 6.56, 6.87 , 6.94-6.96, 7.02, 7.16-7.21, 7.30, 7.41, 7.50-7.54, 7.57-7.65.

Example 16 (4):
3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (oxan-2-ylmethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate HPLC retention time (minutes) ): 1.10;
^{1 1} H-NMR (CD ₃ OD): δ 1.26, 1.39-1.55, 1.68, 1.82, 2.06-2.11, 2.57-2.61, 2.92-2.95, 3.23-3.30, 3.51, 3.70, 3.87, 4.10, 4.18, 4.55, 6.20 , 6.56, 6.87, 6.93-6.96, 7.02, 7.16-7.21, 7.28, 7.38, 7.49-7.53, 7.58-7.63.

Example 16 (5): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (propan-2-yl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] TLC propanoate: Rf 0.31 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.04, 1.98-2.21, 2.67, 2.89-3.01, 4.10-4.24, 4.55-4.66, 6.22, 6.59, 6.85-6.92, 7.07, 7.16-7.28, 7.38-7.57, 7.76.

Example 16 (6): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (2-methylpropyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propane Acid TLC: Rf 0.34 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 0.91, 1.57, 2.08-2.15, 2.67, 2.97, 3.30, 4.10-4.24, 4.62, 6.20, 6.57, 6.83-6.92, 7.08, 7.16-7.25, 7.31, 7.40-7.47, 7.51-7.60.

Example 16 (7): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (cyclopropylmethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid TLC: Rf 0.79 (ethyl acetate);
^{1 1} H-NMR (CDCl ₃ ): δ 0.09-0.13, 0.38-0.43, 0.80-0.90, 2.09-2.18, 2.67, 2.97, 3.42, 4.11-4.23, 4.63, 6.22, 6.58, 6.86-6.93, 7.14-7.26, 7.33, 7.44, 7.55, 7.63.

Example 16 (8): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (2-phenylethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propane Acid TLC: Rf 0.74 (ethyl acetate);
^{1 1} H-NMR (CDCl ₃ ): δ 2.07-2.21, 2.64-2.71, 2.74-2.81, 2.94-3.01, 3.72-3.80, 4.11-4.24, 4.63, 6.22, 6.59, 6.81-6.93, 7.09-7.26, 7.31- 7.45, 7.51-7.60.

Example 17: N- (3-bromophenyl) -N- (2-oxopropyl) benzenesulfonamide Hydrogenated in a DMF (6 mL) solution of the compound (1.00 g) prepared in Example 9 under ice-cooling. Sodium (60% in mineral oil, 141 mg) was added and stirred at room temperature. After 30 minutes, chloroacetone (0.52 mL) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 50: 50) to give the title compound (1.10 g) having the following physical property values.
TLC: Rf 0.42 (Hexane: Ethyl acetate = 2: 1)

Example 18: N- (3-bromophenyl) -N- (2-hydroxy-2-methylpropyl) benzenesulfonamide in THF (3 mL) solution of the compound (313 mg) prepared in Example 17 under ice-cooling. Methyl magnesium bromide (0.95 M THF solution, 1.0 mL) was added and stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 50: 50) to give the title compound (50 mg) having the following physical property values.
TLC: Rf 0.58 (hexane: ethyl acetate = 1: 1).

Example 19: 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl- (2-hydroxy-2-methylpropyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl ] Proanoic acid Instead of the N- (3-bromophenyl) benzenesulfonamide used in Example 10, the compound prepared in Example 18 is used, and the same operation as in Example 10 → Example 11 is performed. Obtained the title compound having the following physical property values.
HPLC retention time (minutes): 0.93;
^{1 1} H-NMR (CD ₃ OD): δ 1.18, 2.06-2.10, 2.58-2.62, 2.92-2.96, 3.66, 4.10, 4.18, 4.54, 6.20, 6.55, 6.87, 6.95, 6.99, 7.05, 7.17-7.21, 7.25 , 7.35, 7.46-7.54, 7.60.

Examples 20 (1) to (4)
Example 17 → Example using a halide compound corresponding to the chloroacetone used in Example 17 in place of the N- (3-bromophenyl) benzenesulfonamide used in Example 10. Example 10 → The following compound of Example was obtained by subjecting the same operation as in Example 11.

Example 20 (1): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (methyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention Hours (minutes): 0.99;
^{1 1} H-NMR (CDCl ₃ ): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 3.20, 4.10, 4.19, 4.55, 6.24, 6.57, 6.87, 6.93-7.00, 7.08, 7.17-7.20, 7.27, 7.36, 7.50-7.56, 7.63.

Example 20 (2): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (ethyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention Hours (minutes): 1.01;
^{1 1} H-NMR (CDCl ₃ ): δ 1.07, 2.06-2.11, 2.57-2.61, 2.92-2.96, 3.66, 4.11, 4.19, 4.55, 6.22, 6.57, 6.87, 6.92-6.96, 7.01, 7.16-7.21, 7.29, 7.39, 7.50-7.54, 7.59-7.65.

Example 20 (3): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (benzyl) amino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention Hours (minutes): 1.07;
^{1 1} H-NMR (CDCl ₃ ): δ 2.04-2.09, 2.57-2.61, 2.91-2.95, 4.08, 4.16, 4.52, 4.80, 6.14, 6.48, 6.85-6.89, 6.93-6.96, 7.14-7.28, 7.54-7.58, 7.63-7.69.

Example 20 (4): 3- [2-[(E, 3R) -5- [3- [benzenesulfonyl (2,2,2-trifluoroethyl) amino] phenyl] -3-hydroxypenta-4- Enoxy] Phenyl] Proanoate TLC: Rf 0.49 (Hexane: Ethyl Acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 2.08-2.17, 2.62-2.70, 2.94-3.00, 4.11-4.26, 4.62, 6.21, 6.57, 6.83-6.93, 7.10, 7.17-7.25, 7.36, 7.47, 7.57-7.63.

Example 21: (R) -1- (3-bromophenyl) -2-phenylethane-1-ol 1- (3-bromophenyl) -2-phenylethanone (CAS registration number: 40396-53-0) 2. In a solution of (2.00 g) in THF (70 mL), at −20 ° C., (R) -methyloxazaborolidine (1.0 M toluene solution, 3.6 mL) and borane dimethyl sulfide (2.0 M THF solution, 3. 6 mL) was added, and the mixture was stirred at the same temperature for 1 hour. Methanol (1 mL) was added to the reaction solution at −20 ° C., and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) to give the title compound (1.91 g, 96% ee) having the following physical characteristics. The obtained compound was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IA (10 mm × 250 mm), mobile phase: CO ₂ : acetonitrile: methanol = 90: 9: 1, flow velocity: 30 mL / min, pressure: 100 bar, wavelength: As a result of analysis at 220 nm, column temperature: 35 ° C.), the holding time was 5.6 minutes.
HPLC retention time (minutes): 1.08.

Example 22: Isopropyl 3-(2-(((R, E) -3-hydroxy-5-(3-((R) -1-hydroxy-2-phenylethyl) phenyl) penta-4-ene-1) -Il) Oxy) Phenyl) Propanoate Instead of the N- (3-bromophenyl) benzenesulfonamide used in Example 10, the compound prepared in Example 21 is used, and the same operation as in Example 10 is performed. As a result, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.21.

Example 23: 3- [2-[(E, 3R) -3-hydroxy-5-[3-[(1R) -1-hydroxy-2-phenylethyl] phenyl] penta-4-enoxy] phenyl] propane Acid of the propanoate of the propano-2-yl 3- [2-[(E, 3R) -5-[3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate used in Example 11. Instead, the compound produced in Example 22 was used and subjected to the same operation as in Example 11 to obtain a title compound having the following physical property values.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CD ₃ OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.28, 6.62, 6.86, 6.94, 7.10-7.31.

Example 24: 3- [2-[(E, 3R) -3-hydroxy-5-[3-[(1S) -1-hydroxy-2-phenylethyl] phenyl] penta-4-enoxy] phenyl] propane Acid Instead of (R) -methyloxazaborolidin used in Example 21, (S) -methyloxazaborolidine was used in place of N- (3-bromophenyl) benzenesulfonamide used in Example 10. By subjecting the same operation as in Example 21 → Example 10 → Example 11 using the corresponding halide compound, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.97;
^{1 1} H-NMR (CD ₃ OD): δ 2.08-2.13, 2.58-2.62, 2.93-2.98, 3.06, 4.11, 4.19, 4.56, 4.84, 6.27, 6.61, 6.86, 6.94, 7.10-7.31.

Example 25: 3- [2-[(E, 3R) -3-hydroxy-5-[3-[(2R) -2-hydroxy-2-phenylethyl] phenyl] penta-4-enoxy] phenyl] propane Acid 2- (3-Bromophenyl) -1-phenylethanone (CAS registration number: 27798-44-3) was used in place of 1- (3-bromophenyl) -2-phenylethanone used in Example 21. By using a halide compound corresponding to the N- (3-bromophenyl) benzenesulfonamide used in Example 10 and performing the same operation as in Example 21 → Example 10 → Example 11. , The title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.64-2.68, 2.94-3.05, 4.10-4.21, 4.59-4.64, 4.92, 6.27, 6.61, 6.86-6.91, 7.05-7.24, 7.27-7.37.

Example 26: 3- [2-[(E, 3R) -3-hydroxy-5-[3-[(2S) -2-hydroxy-2-phenylethyl] phenyl] penta-4-enoxy] phenyl] propane Acid Instead of (R) -methyloxazaborolidin used in Example 25, (S) -methyloxazaborolidine was used in place of N- (3-bromophenyl) benzenesulfonamide used in Example 10. The title compound having the following physical property values was obtained by subjecting the same operation as in Example 25 to the corresponding halide compound.
HPLC retention time (minutes): 0.98;
^{1 1} H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.63-2.67, 2.94-3.05, 4.10-4.22, 4.59-4.64, 4.91, 6.27, 6.61, 6.86-6.91, 7.06-7.08, 7.14-7.24, 7.28- 7.38.

Example 27: A solution of 1- (3-bromophenyl) -3-phenylpropan-1-ol 3-bromobenzaldehyde (500 mg) in THF (13.5 mL) was cooled to 0 ° C. and phenylmagnesium chloride (1. 0 M THF solution (3.5 mL) was added and the reaction mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was poured into saturated ammonium chloride solution and extracted with methyl-tert-butyl ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 2: 1) to give the title compound (610 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 1.85, 1.98-2.15, 2.65-2.80, 4.65-4.69, 7.18-7.31, 7.39-7.42, 7.51.

Example 28: 3- [2-[(E, 3R) -3-hydroxy-5-[3- (1-hydroxy-3-phenylpropyl) phenyl] penta-4-enoxy] phenyl] propanoic acid Example 10 By using the compound produced in Example 27 in place of the N- (3-bromophenyl) benzenesulfonamide used in Example 27 and performing the same operation as in Example 10 → Example 11, the following physical property values are obtained. The title compound having the above was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 1.82-2.03, 2.36-2.40, 2.47-2.63, 2.81-2.85, 3.96-4.09, 4.46-4.51, 6.22, 6.54, 6.69-6.79, 6.98-7.29.

Example 29: 1- (3-Bromophenyl) -2-methyl-2-phenylpropan-1-ol 1- (3-Bromophenyl) -2-phenyl-ethaneone (CAS registration number: 40396-53-0) To a solution of (220 mg) toluene (0.4 mL), potassium hydroxide (179 mg) and 18-crown-6-ether (4 mg) and methyl iodide (0.29 mL) were added and the reaction mixture was mixed at 70 ° C. for 4 hours. Stirred. Water was added to the reaction mixture, and the mixture was extracted with 2-methoxy-2-methylpropane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Sodium borohydride (61 mg) was added to the obtained residual methanol (1.5 mL) solution, and the reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residual silica gel column chromatography (hexane: ethyl acetate = 9: 1) was used for purification to give the title compound (129 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.15 (conditions).

Example 30: 3- [2-[(E, 3R) -3-hydroxy-5-[3- (1-hydroxy-2-methyl-2-phenylpropyl) phenyl] penta-4-enoxy] phenyl] propane Acid Instead of the N- (3-bromophenyl) benzenesulfonamide used in Example 10, the compound prepared in Example 29 was used, and the same operation as in Example 10 → Example 11 was performed. , The title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 2.08-2.13, 2.64-2.68, 2.94-2.97, 4.08-4.21, 4.59, 4.75, 6.15, 6.56, 6.86-6.91, 6.97-7.00, 7.09, 7.15-7.25, 7.30- 7.38.

Example 31: 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanamide The compound prepared in Example 11 ( To a solution of 50 mg) of THF (1 mL) was added triethylamine (0.021 mL) and isobutylchloroformate (0.016 mL) under ice-cooling, and the reaction mixture was stirred at 0 ° C. for 10 minutes. Ammonia (0.5 M 1,4-dioxane solution, 0.4 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1) to give the title compound (38 mg) having the following physical properties. ..
HPLC retention time (minutes): 0.88;
^{1 1} H-NMR (CDCl ₃ ): δ 2.09-2.21, 2.54-2.63, 3.01, 4.13-4.23, 4.59, 5.70, 6.36, 6.54, 6.87-6.94, 7.00-7.22, 7.40-7.53, 7.79-7.82, 7.93.

Examples 32 (1) to (3)
The following Example compound was obtained by subjecting to the same operation as in Example 31 using an amine compound corresponding to the ammonia used in Example 31.

Example 32 (1): N- [3-[(E, 3R) -3-hydroxy-5- [2- (3-morpholine-4-yl-3-oxopropyl) phenoxy] penta-1-enyl] Phenyl] Benzene Sulfonamide HPLC Retention Time (minutes): 0.94;
^{1 1} H-NMR (CDCl ₃ ): δ 2.09-2.19, 2.60-2.65, 2.92-2.99, 3.41, 3.50-3.70, 4.09-4.23, 4.57, 6.30, 6.52, 6.85-6.91, 7.02-7.20, 7.40-7.56, 7.78-7.81.

Example 32 (2): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -N, N-dimethylpropane Amide HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 2.09-2.19, 2.60-2.65, 2.86-3.03, 4.09-4.22, 4.55, 6.33, 6.51, 6.84-6.91, 6.98-7.00, 7.12-7.20, 7.23-7.26, 7.40- 7.52, 7.78-7.83, 7.98.

Example 32 (3): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -N-methylpropaneamide HPLC Retention time (minutes): 0.90;
^{1 1} H-NMR (CDCl ₃ ): δ 2.07-2.19, 2.41-2.53, 2.82, 2.93-2.97, 4.10-4.22, 4.60, 5.58, 6.31, 6.54, 6.86-6.90, 7.02-7.20, 7.40-7.54, 7.78.

Example 33: 3- [2-[(3S) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid

To a solution of the compound (1.1 g) prepared in Example 11 in methanol (10 mL) was added 5% palladium-carbon (200 mg), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 70: 30 → ethyl acetate: methanol = 95: 5) to have the following physical properties. The title compound (1.05 g) having a value was obtained.
TLC: Rf 0.30 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.

Example 34: 3- [2-[(3S) -5- [3- (benzylamino) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid 3- [2-[(E) used in Example 33 , 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] Using the compound prepared in Example 12 (6) instead of propanoic acid, Example 33. The following Example compounds were obtained by subjecting to the same operation as in the above.
HPLC retention time (minutes): 0.81;
^{1 1} H-NMR (CD ₃ OD): δ 1.74-1.90, 2.00, 2.51-2.55, 2.59, 2.70, 2.85-2.89, 3.85, 4.07-4.16, 4.31, 6.47-6.56, 6.85, 6.92, 7.00, 7.13-7.23 , 7.28-7.32, 7.36-7.38.

Example 35: Isopropyl 3-(2-(((S) -3-hydroxy-5-(3-((R) -1-hydroxy-2-phenylethyl) phenyl) pentyl) oxy) phenyl) propanoate Example To a solution of the compound (782 mg) prepared in No. 22 in THF (10 mL) was added p-toluenesulfonyl hydrazide (2.66 g) and sodium acetate (1.17 g) at room temperature, and the mixture was stirred at 80 ° C. for 19 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 1: 1) to give the title compound (515 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.22.

Example 36: 3- [2-[(3S) -3-hydroxy-5-[3-[(1R) -1-hydroxy-2-phenylethyl] phenyl] pentoxy] phenyl] propanoic acid

Instead of the propano-2-yl 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate used in Example 11. By subjecting the compound produced in Example 35 to the same operation as in Example 11, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CD ₃ OD): δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.82, 6.85, 6.94, 7.08-7.23 ..

Example 37: 3- [2-[(3S) -3-hydroxy-5-[3-[(1S) -1-hydroxy-2-phenylethyl] phenyl] pentoxy] phenyl] propanoic acid

Equivalent to (S) -methyloxazaborolidin instead of (R) -methyloxazaborolysine used in Example 21 instead of N- (3-bromophenyl) benzenesulfonamide used in Example 10 The title compound having the following physical property values was obtained by subjecting to the same operation as in Example 21 → Example 10 → Example 35 → Example 11 using the halide compound.
HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CD ₃ OD): δ 1.74-1.81, 1.89, 2.02, 2.52-2.56, 2.66, 2.79, 2.86-2.90, 2.94, 3.05, 3.86, 4.08-4.19, 4.81, 6.85, 6.94, 7.08-7.23 ..

Example 38: Isopropyl 3-(2-((3R) -3-hydroxy-3- (2- (3- (phenylsulfonamide) phenyl) cyclopropyl) propoxy) phenyl) propanoate The compound prepared in Example 10 ( A 50 mg) solution of dichloromethane (2 mL) was cooled to 0 ° C., diethylzinc (1 M hexane solution, 0.5 mL) was added, followed by diiodomethane (128 mg), and the resulting reaction mixture was cooled at 0 ° C. for 1.5 hours. Stirred. A saturated aqueous solution of ammonium chloride was added at 0 ° C., and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 2: 1) to give the title compound (15 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.10.

Example 39: 3- [2-[(3R) -3- [2- [3- (benzenesulfonamide) phenyl] cyclopropyl] -3-hydroxypropoxy] phenyl] propanoic acid Propane used in Example 11- 2-Il 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] The compound prepared in Example 38 instead of propanoate. By subjecting to the same operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.92;
^{1 1} H-NMR (CD ₃ OD): δ 0.85-0.92, 1.03-1.08, 1.72-1.75, 2.03-2.09, 2.57, 2.91, 4.06-4.15, 6.68-6.69, 6.73-6.75, 6.84-6.89, 7.06, 7.14 -7.20, 7.44-7.57, 7.72-7.74.

Example 40: 5-((3-nitrobenzyl) sulfonyl) -1-phenyl-1H-tetrazole 5-[(3-nitrobenzyl) thio] -1-phenyl-1H-tetrazole [J. Org. Chem. (2001), 80, pp. 11611-11617] (8.50 g) of acetonitrile (150 mL) and ethanol (150 mL) solution cooled to 0 ° C., aqueous hydrogen peroxide solution (35%, 26 mL) of ammonium molybdate tetrahydrate (3.35 g). Was added dropwise over 10 minutes. The reaction mixture was stirred at 0 ° C. for 2 hours and at room temperature for 2.5 hours. The reaction mixture was cooled to 0 ° C. again, and an aqueous sodium thiosulfate solution (1M, 150 mL) was slowly added over 20 minutes. The mixture was concentrated under reduced pressure, the residue was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained oil was suspended in a mixed solvent of hexane and ethyl acetate, and the blue solid was collected by filtration. The solid was dissolved in dichloromethane, the resulting solid was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (7.71 g) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 5.12, 7.46-7.64, 7.82, 8.27, 8.35.

Example 41: (R) -1-((tert-butyldimethylsilyl) oxy) -4-((4-methoxybenzyl) oxy) butane-2-ol (R) -4-[(4-methoxybenzyl)) Oxy] Butane-1,2-diol (CAS Registry Number: 213978-61-1) (13.5 g) was added to a solution of DMF (300 mL) with DMAP (0.73 g) and imidazole (6.08 g) for reaction. The mixture was stirred at 0 ° C. for 5 minutes. Chloro-tert-butyl-dimethylsilane (8.93 g) was added, and the mixture was stirred overnight at room temperature. After diluting the reaction solution by adding ethyl acetate, the organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the title compound (18.1 g) having the following physical properties was obtained. Got
^{1 1} H-NMR (CDCl ₃ ): δ 0.02, 0.83, 1.65-1.71, 2.73, 3.62-3.41, 3.74, 3.74-3.76, 4.39, 6.82, 7.18-7.21.

Example 42: (R) -1-((tert-butyldimethylsilyl) oxy) -4-((4-methoxybenzyl) oxy) butane-2-ylbenzoate The compound (5.60 g) prepared in Example 41. A solution of pyridine (27 mL) in dichloromethane (55 mL) was cooled to 0 ° C. and N, N-diisopropylethylamine (27 mL) and DMAP (0.2 g) were added. Benzyl chloride (2.5 mL) was added to the reaction solution, the mixture was stirred overnight at room temperature, and then concentrated under reduced pressure. The obtained residue was poured over ethyl acetate, the organic layer was washed with 1M hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 7: 3) to give the title compound (6.31 g) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 0.00, 0.01, 0.85, 2.02-2.08, 3.53-3.57, 3.76, 3.79, 4.40, 5.27-5.30, 6.81, 7.21, 7.42, 7.53-7.56, 8.01.

Example 43: (R) -1-Hydroxy-4-((4-methoxybenzyl) oxy) butane-2-ylbenzoate A solution of the compound (6.31 g) prepared in Example 42 in THF (170 mL) was added to 0 ° C. Acetic acid (3.6 mL) and tetrabutylammonium fluoride (1.0 M THF solution, 21.2 mL) were added, and the mixture was stirred overnight at room temperature. The obtained residue was poured over ethyl acetate, the organic layer was washed with saturated aqueous ammonia and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 1) to give the title compound (4.10 g) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 2.06-2.09, 2.57, 3.54-3.65, 3.78, 3.80-3.86, 4.41-4.46, 5.27-5.30, 6.84, 7.23, 7.43, 7.56, 8.02.

Example 44: (R) -4-((4-methoxybenzyl) oxy) -1-oxobutane-2-ylbenzoate pyridinium dichromate (10.6 g) and molecular sieve (trade name) (21.7 g) Suspended in dichloromethane (30 mL), a dichloromethane solution (100 mL) of the compound (3.1 g) prepared in Example 43 was added dropwise to the solution. After stirring at room temperature for two and a half hours, the mixture was diluted with diethyl ether and filtered. The filtrate was concentrated under reduced pressure to give the title compound having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 2.27-2.40, 3.57-3.70, 3.76, 4.43, 5.40, 6.82, 7.15-7.24, 7.45, 7.60, 8.03, 9.64.

Example 45: (R, E) -5-((4-methoxybenzyl) oxy) -1- (3-nitrophenyl) penta-1-ene-3-ylbenzoate The compound prepared in Example 40 (3. 56 g) of a solution of THF (70 mL) was cooled to −70 ° C. and potassium hexamethyldisilazide (0.5 M toluene solution, 22.5 mL) was added. The reaction mixture was stirred at −70 ° C. for 30 minutes, a solution of the compound (3.09 g) prepared in Example 44 in THF (20 mL) was added dropwise over 5 minutes, and the reaction solution was stirred at room temperature overnight. After diluting the reaction solution by adding ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 0). → Purification by 1: 1) gave the title compound (2.23 g) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 2.11-2.24, 3.60, 3.75, 6.81, 7.22, 7.43-7.47, 7.56-7.63, 8.04-8.09, 8.21.

Example 46: (R, E) -5-hydroxy-1- (3-nitrophenyl) penta-1-en-3-ylbenzoate, or (S, E) -5-hydroxy-1- (3-nitro) Phenyl) penta-1-en-3-ylbenzoate In a solution of the compound (2.23 g) prepared in Example 45 in dichloromethane (100 mL) and phosphate buffer (pH 7,100 mL) at room temperature, 2,3-dichloro-5. , 6-Dicyano-1,4-benzoquinone (2.26 g) was added, and the mixture was vigorously stirred at room temperature for 3.5 hours. The reaction mixture was poured over ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 4) to obtain a mixture of the title compounds (1.25 g). The obtained mixture was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IA (20 mm × 250 mm), mobile phase: CO ₂ : methanol = 90:10, flow velocity: 100 mL / min, pressure: 120 bar, wavelength: 254 nm, column temperature. : 35 ° C.) was used for optical resolution. The optically active substance obtained under the above optical resolution conditions was SFC (column used: Daicel Co., Ltd. CHIRALPAK-IA (10 mm × 250 mm), mobile phase: CO ₂ : acetonitrile: methanol = 75: 22.5: 2.5, flow velocity. As a result of analysis at: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.), (R, E) -5-hydroxy-1- (3-nitrophenyl) penta-1-en-3- The retention times for ylbenzoate and (S, E) -5-hydroxy-1- (3-nitrophenyl) penta-1-en-3-ylbenzoate were 5.4 and 8.5 minutes, respectively.
^{1 1} H-NMR (CDCl ₃ ): δ 2.04, 2.10-2.14, 3.77-3.82, 5.92-5.95, 6.47, 6.79, 7.46-7.51, 7.60, 7.68, 8.08-8.12, 8.26.

Example 47: Methyl 2- (2-Hydroxyphenyl) -2-methylpropanoate Methyl 2- (2-hydroxyphenyl) acetate (CAS registration number: 22446-37-3) (1.5 g) in THF (120 mL) ) Lithium diisopropylamide (2.0 M THF solution, 18 mL) was added to the solution at −78 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Methyl iodide (5.2 g) was added to the reaction solution at −78 ° C., and the mixture was stirred at room temperature for 30 minutes. Water (40 mL) and acetic acid (1 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue (1.8 g) was dissolved in THF (150 mL), lithium diisopropylamide (2.0 M THF solution, 10 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Methyl iodide (2.85 g) was added to the reaction solution at −78 ° C., and the mixture was stirred at room temperature for 30 minutes. Water (40 mL) and acetic acid (1 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7: 1) to give the title compound (538 mg) having the following physical property values.
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.42, 3.51, 6.70-6.83, 7.05, 7.19, 9.49.

Example 48: Methyl 1- (2-hydroxybenzyl) cyclopropane-1-carboxylate in a solution of cyclopropyl carbonitrile (CAS registration number: 5500-21-0) (3.35 g) in THF (50 mL) at room temperature. Sodium bis (trimethylsilyl) amide (1.0 M THF solution, 75 mL) was added and stirred for 20 minutes. To the reaction solution was added 1- (chloromethyl) -2-methoxybenzene (CAS Registry Number: 7035-02-1) (7.83 g) at room temperature, and the mixture was stirred under heating under reflux for 3 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a crude product (6.00 g) of a nitrile compound. Concentrated sulfuric acid (20 mL) was added to a solution of the obtained crude product of the nitrile compound (4.50 g) in methanol (50 mL) at room temperature, and the mixture was stirred under heating under reflux for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Ice water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product (3.20 g) of an ester compound. Boron tribromide (1.0 M dichloromethane solution, 18.2 mL) was added dropwise to a solution of the obtained crude ester compound (2.00 g) in dichloromethane (30 mL) at −10 ° C., and the mixture was stirred at room temperature for 1 hour. did. After concentrating the reaction solution under reduced pressure, the obtained residue is subjected to high performance liquid chromatography (mobile phase A (0.1% trifluoroacetic acid (hereinafter abbreviated as TFA) aqueous solution): mobile phase B (0.1% TFA / acetonitrile). By preparative purification in = 95: 5 → 5:95), the title compound (550 mg) having the following physical property values was obtained.
^{1 1} H-NMR (CDCl ₃ ): δ 1.11, 1.39, 2.90, 3.67, 6.87, 6.99, 7.18, 8.45.

Example 49: THF of methyl 4- (2-hydroxyphenyl) -2,2-dimethylbutanoate methyl 4- (2-hydroxyphenyl) butanoate (CAS registration number: 93108-07-7) (3.00 g) A lithium diisopropylamide solution (2.0 M THF solution, 22.5 mL) was added to the (150 mL) solution at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (6.3 g) was added to the reaction solution at −78 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is preparatively purified by high performance liquid chromatography (mobile phase A (0.1% TFA aqueous solution): mobile phase B (0.1% TFA / acetonitrile) = 95: 5 → 5:95). Obtained the title compound (538 mg) having the following physical property values.
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.17, 1.67-1.73, 2.38-2.43, 3.59, 6.66-6.76, 6.95-7.00, 9.19.

Example 50: THF of methyl 1- (2-methoxyphenethyl) cyclopropane-1-carboxylate bis (cyclopentadienyl) titanium (IV) zinc (CAS Registry Number: 1271-19-8) (34.6 g) Zinc (18.2 g) was added to the (200 mL) solution at room temperature, and the mixture was stirred at the same temperature for 1 hour. Methyl 2- (1-acetoxymethyl) -2-propenoate (CAS Registry Number: 30982-08-2) (11.0 g) and 1- (chloromethyl) -2-methoxybenzene (CAS Registry Number) in the reaction solution at room temperature. A solution of THF (200 mL) of No .: 7035-02-1) (10.9 g) was added, and the mixture was stirred overnight at the same temperature. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1 → 2: 1) to obtain a crude product (13.0 g) of the ester compound. Palladium acetate (II) and diazomethane (0.5 M diethyl ether solution, 32.6 mL) were added to a solution of the obtained ester compound (3.00 g) as a crude product in diethyl ether (100 mL) at room temperature. The mixture was stirred for 4 hours. Acetic acid (4 mL) and water were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.00 g) having the following physical characteristics.
^{1 1} H-NMR (DMSO-d ₆ ): δ 0.70, 1.21, 1.76-1.88, 2.76-2.87, 3.70, 3.83, 6.80-6.96, 7.11-7.32.

Example 51: Methyl 1- (2-hydroxyphenethyl) cyclopropane-1-carboxylate Boron tribromide (1) in a solution of the compound (3.00 g) prepared in Example 50 in dichloromethane (100 mL) at −78 ° C. A 0.0 M dichloromethane solution (38.4 mL) was added dropwise, and the mixture was stirred at the same temperature for 5 hours. Methanol (30 mL) and water were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to preparative purification by high performance liquid chromatography (mobile phase A (0.5% aqueous ammonium hydrogencarbonate solution): mobile phase B (acetonitrile) = 80:20 → 25:75) to obtain the following. The title compound (515 mg) having a physical property value was obtained.
^{1 1} H-NMR (DMSO-d ₆ ): δ 0.73, 1.06, 1.67-1.79, 2.58-2.70, 3.58, 6.63-6.80, 6.95-7.01, 9.17.

Example 52: Ethyl (E) -3- (2- (benzyloxy) -5-fluorophenyl) acrylate Sodium hydride (60% in mineral oil, 1.80 g) is suspended in DMF (30 mL) to prepare a solution. It was cooled to 0 ° C. After adding triethylphosphonoacetate (10.0 g) and stirring at 0 ° C. for 30 minutes, DMF (8.70 g) of 2-benzyloxy-5-fluoro-benzaldehyde (CAS Registry Number: 312314-37-7) (8.70 g) was added. 10 mL) The solution was added dropwise and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (13.2 g) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 1.33, 4.24, 5.13, 6.47, 6.85-7.00, 7.21-7.41, 7.99-8.05.

Example 53: Ethyl 3- (5-fluoro-2-hydroxyphenyl) propanoate Palladium on carbon (1.95 g) was added to a solution of the compound (11.0 g) prepared in Example 52 in ethanol (18 mL) to create a hydrogen atmosphere. Below, the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to give the title compound (5.8 g) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 1.24, 2.71, 2.86, 4.15, 6.77-6.83, 7.23.

Example 54: (R, E) -5-(2-((E) -3-methoxy-3-oxopropa-1-ene-1-yl) phenoxy) -1- (3-nitrophenyl) penta-1 -En-3-yl benzoate (R, E) -5-hydroxy-1- (3-nitrophenyl) penta-1-en-3-yl benzoate (110 mg), methyl (E)-produced in Example 46. Diisopropyl azodicarboxylate (hereinafter referred to as DIAD) in a solution of 3- (2-hydroxyphenyl) propa-2-enoate (CAS registration number: 6236-69-7) (90 mg) and triphenylphosphine (130 mg) in THF (1 mL) (Abbreviation) (0.1 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 2) to give the title compound (200 mg) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 2.43-2.55, 3.78, 4.24, 5.94-5.98, 6.46-6.53, 6.82, 6.90, 6.96, 7.29-7.33, 7.44-7.51, 7.57-7.60, 7.68, 8.00, 8.07- 8.10, 8.23-8.24.

Example 55: (R, E) -1- (3-aminophenyl) -5-(2-((E) -3-methoxy-3-oxoprop-1-ene-1-yl) phenoxy) penta-1 -En-3-yl benzoate Second tin chloride (310 mg) was added to an ethanol solution (7 mL) of the compound (160 mg) prepared in Example 54, and the mixture was stirred at 70 ° C. for 3.5 hours. After returning the reaction solution to room temperature, the reaction mixture was opened over ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 2) to give the title compound (120 mg) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 2.39-2.52, 3.66, 3.79, 4.20, 5.90, 6.28, 6.53, 6.57-6.59, 6.68, 6.73, 6.79, 6.89, 6.94, 7.09, 7.28-7.32, 7.42-7.47, 7.49-7.50, 7.54-7.58, 8.01, 8.05-8.07.

Example 56: (R, E) -5-(2-((E) -3-methoxy-3-oxopropa-1-ene-1-yl) phenoxy) -1- (3- (phenylsulfonamide) phenyl ) Penta-1-en-3-ylbenzoate A dichloromethane solution (1 mL) of the compound (60 mg) and pyridine (0.016 mL) prepared in Example 55 was cooled to 0 ° C., and phenylsulfonyl chloride (0.018 mL) was added. In addition, the mixture was stirred overnight while returning to room temperature. 1M hydrochloric acid and saturated brine were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 1) to give the title compound (62 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 2.41-2.45, 3.87, 4.18-4.22, 5.84-5.88, 6.30-6.34, 6.51, 6.64, 6.89, 6.99, 7.05-7.19, 7.30-7.34, 7.38-7.50, 7.50- 7.52, 7.56-7.59, 7.74-7.77, 8.04-8.07.

Example 57: (E) -3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propa-2-enoic acid A 1 M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound (62 mg) prepared in Example 56 in THF (1.5 mL) and methanol (0.5 mL), and the mixture was stirred at room temperature for 7 hours. 1M hydrochloric acid and saturated brine were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 0 → 9: 1) to give the title compound (29 mg) having the following physical characteristics.
HPLC retention time (minutes): 0.89;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.91-2.04, 4.10-4.22, 4.36, 5.12, 6.21-6.25, 6.44, 6.55, 6.93-6.99, 7.08-7.11, 7.16, 7.36-7.40, 7.52-7.55, 7.58-7.61, 7.66-7.68, 7.75-7.77, 7.85, 10.27, 12.31.

Example 58: N- [3-[(E, 3R) -5- [2- (2-cyanoethyl) phenoxy] -3-hydroxypenta-1-enyl] phenyl] benzenesulfonamide Methyl used in Example 54 By using the corresponding phenol compound instead of (E) -3- (2-hydroxyphenyl) propa-2-enoate and performing the same operation as in Example 54 → Example 55 → Example 56. The title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CDCl ₃ ): δ 2.07-2.19, 2.60-2.65, 2.89-3.00, 4.10-4.23, 4.58, 6.24, 6.44, 6.56, 6.89-6.95, 7.10-7.27, 7.42-7.46, 7.52-7.56, 7.75-7.78.

Example 59: Methyl 1- [2- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] ethyl] cyclopropane-1 -Carboxylate Example 54-> Example 55-> using the phenolic compound prepared in Example 51 instead of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used in Example 54. By subjecting to the same operation as in Example 56, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 0.71, 1.22, 1.79-1.83, 2.07-2.15, 2.44, 2.77-2.81, 3.65, 4.10-4.23, 6.24, 6.44, 6.55, 6.83-6.94, 7.08-7.20, 7.41- 7.45, 7.51-7.55, 7.75-7.77.

Example 60: Methyl 4- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -2,2-dimethylbutanoate Example 54 → Example 55 → Example 56 using the phenolic compound prepared in Example 49 in place of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used in Example 54. By subjecting to the same operation as in the above, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 1.53, 1.56, 2.33-2.45, 3.63, 4.10-4.19, 5.95, 6.46, 6.71-6.91, 7.17-7.24, 7.45-7.52, 7.57-7.68.

Examples 61 (1) to (8)
Example 54-> Example 55-> Example 56-> Example 57, using the corresponding phenolic compound in place of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used in Example 54. The following Example compounds were obtained by subjecting to the same operation as in the above.

Example 61 (1): (E) -3- [4-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propa-2 − Enoic acid HPLC retention time (minutes): 0.85;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.84-1.92, 4.06-4.17, 4.32-4.33, 5.07, 5.60-6.00, 6.10, 6.21, 6.37, 6.44, 6.94-6.97, 7.09-7.11, 7.16, 7.48- 7.63, 7.75, 10.27, 12.15.

Example 61 (2): 3- [4-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) ): 0.86;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.80-1.84, 1.87-1.96, 2.48, 2.74, 3.95-4.01, 4.01-4.08, 4.28-4.34, 5.04, 6.21, 6.43, 6.82-6.94, 6.93-6.96, 7.08-7.13, 7.17, 7.51-7.56, 7.57-7.59, 7.75-7.78, 10.27, 12.04.

Example 61 (3): (E) -3- [3-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propa-2 − Enoic acid HPLC retention time (minutes): 0.89;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.83-1.98, 4.06-4.17, 4.31-4.35, 5.06, 6.20-6.25, 6.44, 6.54, 6.94-6.99, 7.09-7.11, 7.17, 7.23-7.26, 7.31, 7.52-7.61, 7.75-7.77, 10.27, 12.35.

Example 61 (4): 3- [3-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) ): 0.89;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.81-1.95, 2.51, 2.78, 4.31, 5.05, 6.21, 6.43, 6.73-6.79, 6.93-6.96, 7.09-7.10, 7.14-7.18, 7.52-7.55, 7.58- 7.61, 7.75-7.78, 10.25, 12.10.

Example 61 (5): 2- [3-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -2-methylpropanoic acid HPLC Retention time (minutes): 0.93;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.44, 1.81-1.97, 3.99-4.10, 4.30-4.35, 5.05, 6.21, 6.44, 6.79-6.82, 6.84-6.85, 6.88-6.90, 6.93-6.96, 7.08- 7.10, 7.16, 7.23, 7.51-7.55, 7.57-7.61, 7.75-7.78, 10.25, 12.30.

Example 61 (6):
2- [4-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -2-methylpropanoic acid HPLC retention time (minutes): 0 .92;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.44, 1.83-1.93, 3.99-4.08, 4.29-4.33, 5.04, 6.21, 6.42, 6.86-6.88, 6.93-6.95, 7.07-7.09, 7.16, 7.23-7.25, 7.51-7.55, 7.57-7.60, 7.75-7.77, 10.25, 12.30.

Example 61 (7): 4- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] butanoic acid

HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 1.92-2.00, 2.12, 2.28-2.42, 2.68-2.71, 4.07-4.20, 4.63, 6.85-6.96, 7.08-7.19, 7.40-7.59, 7.59-7.63, 7.75-7.77.

Example 61 (8): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -2,2-dimethylpropane Acid HPLC retention time (minutes): 0.95
^{1 1} H-NMR (CDCl ₃ ): δ 1.21, 2.05-2.15, 2.96, 4.07-4.15, 4.60, 6.23, 6.53, 6.85-7.00, 7.07-7.20, 7.40-7.63, 7.76-7.78.

Example 62: 2- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -2-methylpropanoic acid In Example 54 Example 54 → Example 55 → Example 56 → Example 57 using the phenol compound produced in Example 47 in place of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used. By subjecting to the same operation as in the above, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 1.63-1.65, 2.09-2.14, 4.13-4.21, 4.58, 6.28, 6.52, 6.82-6.84, 7.00-7.06, 7.15-7.19, 7.40-7.62, 7.76-7.78.

Example 63: 1-[[2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] methyl] cyclopropane-1-carboxylic acid Example 54 → Example 55 → Example 56 → using the compound prepared in Example 48 instead of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used in Example 54. By subjecting to the same operation as in Example 57, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CDCl ₃ ): δ 1.38-1.40, 2.11-2.16, 4.13-4.18, 4.58, 6.28, 6.54, 6.85-7.20, 7.38-7.52, 7.74-7.76.

Example 64: 4- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] -2,2-dimethylbutanoic acid Example Example 54 → Example 55 → Example 56 → Example using the compound prepared in Example 49 in place of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used in 54. By subjecting to the same operation as in 57, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 1.28, 1.74-1.91, 2.08-2.17, 2.61, 4.01-4.16, 4.62, 6.22, 6.51, 6.81-7.17, 7.39-7.43, 7.48-7.53, 7.75-7.78.

Example 65: 1- [2- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] ethyl] cyclopropane-1- Carboxylic Acid Example 54 → Example 55 → Example using the phenolic compound prepared in Example 51 instead of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used in Example 54. By subjecting the same operation as in Example 56 to Example 57, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 0.66-0.76, 1.19-1.30, 1.64-1.72, 1.79-1.88, 2.08-2.14, 2.75-2.89, 4.10-4.21, 4.65, 6.28, 6.55, 6.83-6.90, 6.96- 7.00, 7.07-7.18, 7.35-7.39, 7.46-7.52, 7.73-7.76.

Examples 66 (1) to (3)
Using a lactone compound corresponding to 3,4-dihydrocoumarin used in Example 1, the same operation as in Example 1 → Example 54 → Example 55 → Example 56 → Example 57 is applied. As a result, the following Example compounds were obtained.

Example 66 (1): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] -5-bromophenyl] propanoic acid HPLC Retention time (minutes): 0.99;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.10, 2.56-2.60, 2.88-2.92, 4.07-4.19, 4.51, 6.23, 6.53, 6.86-6.88, 6.97-7.00, 7.11-7.19, 7.29-7.32, 7.46 -7.50, 7.54-7.58, 7.76-7.78.

Example 66 (2): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] -5-methylphenyl] propanoic acid HPLC Retention time (minutes): 0.98;
^{1 1} H-NMR (CD ₃ OD): δ 1.92-1.96, 2.13, 2.42-2.46, 2.75-2.79, 3.63-4.03, 4.41, 6.11, 6.42, 6.69, 6.84-6.89, 6.99-7.06, 7.34-7.46, 7.64 -7.66.

Example 66 (3): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] -4-methylphenyl] propanoic acid HPLC Retention time (minutes): 0.97;
^{1 1} H-NMR (CD ₃ OD): δ 1.92-1.97, 2.18, 2.41-2.45, 2.74-2.78, 3.93-4.06, 4.42, 6.11, 6.41, 6.56, 6.64, 6.86-6.92, 7.00-7.07, 7.33-7.46 , 7.64-7.66.

Example 67: 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] -5-fluorophenyl] propanoic acid In Example 54 Example 54 → Example 55 → Example 56 → Example 57 using the phenol compound produced in Example 53 instead of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used. By subjecting to the same operation as in the above, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.94;
^{1 1} H-NMR (CDCl ₃ ): δ 2.09-2.15, 2.67-2.71, 2.93-2.97, 4.10-4.15, 4.59, 6.27, 6.54, 6.77-6.80, 6.84-6.90, 6.95-7.00, 7.08-7.10, 7.16, 7.40-7.44, 7.50-7.55, 7.76-7.78.

Examples 68 (1)-(2)
The corresponding aldehyde compound in place of the 2-benzyloxy-5-fluoro-benzaldehyde used in Example 52 was the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used in Example 54. By substituting the corresponding phenol compound with the same operation as in Example 52 → Example 53 → Example 54 → Example 55 → Example 56 → Example 57, the following Example compound can be obtained. Obtained.

Example 68 (1): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] -6-fluorophenyl] propanoic acid HPLC Retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 2.09-2.15, 2.61-2.65, 2.97-3.01, 4.10-4.17, 4.60, 6.26, 6.54, 6.65-6.70, 6.97-7.00, 7.05-7.18, 7.41-7.44, 7.50- 7.54, 7.76-7.79.

Example 68 (2): 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] -3-fluorophenyl] propanoic acid HPLC Retention time (minutes): 0.94;
^{1 1} H-NMR (CDCl ₃ ): δ 2.09-2.15, 2.69-2.73, 3.01-3.05, 4.22-4.24, 4.67, 6.30, 6.58, 6.95-7.01, 7.10-7.20, 7.42-7.45, 7.51-7.54, 7.77- 7.79.

Example 69: 3- [2-[(E, 3S) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid Methyl used in Example 54 ( The compound prepared in Example 1 instead of E) -3- (2-hydroxyphenyl) propa-2-enoate was used in Example 54 (R, E) -5-hydroxy-1- (3-nitro). Instead of phenyl) penta-1-en-3-yl benzoate, the (S, E) -5-hydroxy-1- (3-nitrophenyl) penta-1-en-3-yl benzoate prepared in Example 54 was used. By subjecting to the same operation as in Example 54 → Example 55 → Example 56 → Example 57, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.93;
^{1 1} H-NMR (CD ₃ OD): δ 2.05-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.17, 4.51-4.56, 6.24, 6.53, 6.86, 6.93, 6.98, 7.12-7.20, 7.45-7.50, 7.56 , 7.75-7.78.

Example 70: 3- [2-[(3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid

By using the compound produced in Example 69 and subjecting it to the same operation as in Example 33, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.93;
^{1 1} H-NMR (CD ₃ OD): δ 1.69-2.02, 2.59-2.75, 2.90-2.96, 3.89, 4.05-4.18, 6.85-7.00, 7.11-7.22, 7.36-7.43, 7.44-7.53, 7.76.

Example 71: Isopropyl (R, E) -3-(2-((5- (3-aminophenyl) -3-((trimethylsilyl) oxy) penta-4-en-1-yl) oxy) phenyl) compound In a solution of the compound (1.00 g) prepared in Example 8 in THF (10 mL), 3-bromoaniline (421 mg), chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1, 1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)] Palladium (II) (0.30 g) and 2M tripotassium phosphate aqueous solution (5.7 mL) were added, and 19 at 70 ° C. Stirred for hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) to give the title compound (515 mg) having the following physical characteristics.
HPLC retention time (minutes): 0.82.

Example 72: Isopropyl (R, E) -3-(2-((5- (3-((4-fluorophenyl) sulfonamide) phenyl) -3-hydroxypenta-4-ene-1-yl) oxy) ) Phenyl) Propanoate Pyridine (0.018 mL), DMAP (2.7 mg) and 4-fluorobenzenesulfonyl chloride (CAS registration number: 349) in a THF (1 mL) solution of the compound (50 mg) prepared in Example 71 at room temperature. −88-2) (25.6 mg) was added, and the mixture was stirred at the same temperature for 16 hours. TBAF (1.0 M THF solution, 0.27 mL) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is preparatively purified by high performance liquid chromatography (mobile phase A (0.1% TFA aqueous solution): mobile phase B (0.1% TFA / acetonitrile) = 90: 0 → 10:90). Obtained the title compound (515 mg) having the following physical property values.
HPLC retention time (minutes): 1.11.

Example 73: 3- [2-[(E, 3R) -5- [3-[(4-fluorophenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid Example 11 Propane-2-yl 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate used in Using the compound produced in Example 72, the same operation as in Example 11 was carried out to obtain a title compound having the following physical property values.
HPLC retention time (minutes): 0.94
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26, 6.55, 6.86, 6.93, 6.99, 7.13-7.25, 7.79-7.82.

Examples 74 (1) to (21)
By using a sulfonyl compound corresponding to 4-fluorobenzenesulfonyl chloride used in Example 72 and performing the same operation as in Example 72 → Example 11, the following Example compound was obtained.

Example 74 (1): 3- [2-[(E, 3R) -5-[3-[(4-chlorophenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.98;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.11, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.55, 6.26, 6.55, 6.86, 6.93, 6.99, 7.13-7.21, 7.48-7.51, 7.71-7.75 ..

Example 74 (2):
3- [2-[(E, 3R) -3-hydroxy-5- [3-[(4-methylphenyl) sulfonylamino] phenyl] penta-4-enoxy] phenyl] propanoate HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.11, 2.37, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11-7.20, 7.27-7.30, 7.63 -7.66.

Example 74 (3): 3- [2-[(E, 3R) -3-hydroxy-5-[3-[[4- (trifluoromethyl) phenyl] sulfonylamino] phenyl] penta-4-enoxy] Phenyl] propanoate HPLC retention time (minutes): 1.01;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.10, 2.57-2.61, 2.91-2.95, 4.10, 4.18, 4.54, 6.27, 6.55, 6.86, 6.93, 6.99, 7.15-7.22, 7.80-7.83, 7.93-7.95 ..

Example 74 (4): 3- [2-[(E, 3R) -5- [3-[(4-butylphenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 1.08;
^{1 1} H-NMR (CD ₃ OD): δ 0.93, 1.31-1.36, 1.55-1.63, 2.06-2.10, 2.57-2.67, 2.91-2.95, 4.11, 4.18, 4.54, 6.24, 6.54, 6.86, 6.93, 6.98, 7.11 -7.20, 7.28-7.30, 7.65-7.68.

Example 74 (5): 3- [2-[(E, 3R) -5-[3-[(3-fluorophenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0.96;
MS (ESI, Pos.): 482 (M + H-H ₂ O) ⁺ .

Example 74 (6): 3- [2-[(E, 3R) -5-[3-[(3-chlorophenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Holding time (minutes): 1.00;
MS (ESI, Pos.): 498 (M + H-H ₂ O) ⁺ .

Example 74 (7): 3- [2-[(E, 3R) -3-hydroxy-5-[3-[(3-methylphenyl) sulfonylamino] phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0.97;
MS (ESI, Pos.): 478 (M + H-H ₂ O) ⁺ .

Example 74 (8): 3- [2-[(E, 3R) -3-hydroxy-5-[3-[[3- (trifluoromethyl) phenyl] sulfonylamino] phenyl] penta-4-enoxy] Phenyl] propanoate HPLC retention time (minutes): 1.00;
MS (ESI, Pos.): 532 (M + H-H ₂ O) ⁺ .

Example 74 (9): 3- [2-[(E, 3R) -5-[3-[(2-fluorophenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0.94;
MS (ESI, Pos.): 482 (M + H-H ₂ O) ⁺ .

Example 74 (10): 3- [2-[(E, 3R) -5-[3-[(2-chlorophenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid HPLC Retention time (minutes): 0.97;
MS (ESI, Pos.): 498 (M + H-H ₂ O) ⁺ .

Example 74 (11): 3- [2-[(E, 3R) -3-hydroxy-5-[3-[(2-methylphenyl) sulfonylamino] phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 0.97;
MS (ESI, Pos.): 478 (M + H-H ₂ O) ⁺ .

Example 74 (12): 3- [2-[(E, 3R) -3-hydroxy-5-[3-[[2- (trifluoromethyl) phenyl] sulfonylamino] phenyl] penta-4-enoxy] Phenyl] propanoate HPLC retention time (minutes): 0.99;
MS (ESI, Pos.): 532 (M + H-H ₂ O) ⁺ .

Example 74 (13): 3- [2-[(E, 3R) -5- [3- (cyclopentylsulfonylamino) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid

HPLC retention time (minutes): 0.93;
^{1 1} H-NMR (CD ₃ OD): δ 1.60-1.67, 1.74-1.81, 1.90-2.05, 2.08-2.13, 2.58-2.62, 2.92-2.96, 3.56, 4.13, 4.20, 4.58, 6.35, 6.62, 6.86, 6.94 , 7.14-7.20, 7.26-7.32.

Example 74 (14): 3- [2-[(E, 3R) -3-hydroxy-5- [3- (oxane-4-ylsulfonylamino) phenyl] penta-4-enoxy] phenyl] propanoate TLC : Rf 0.48 (ethyl acetate);
^{1 1} H-NMR (CDCl ₃ ): δ 1.88-2.00, 2.15-2.20, 2.63-2.74, 2.90-3.02, 3.22-3.35, 4.04, 4.17, 6.38, 6.60, 6.88, 7.13-7.28.

Example 74 (15): 3- [2-[(E, 3R) -5- [3- (benzylsulfonylamino) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate TLC: Rf 0. 55 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 2.13-2.18, 2.67, 2.96, 4.13-4.22, 4.34, 4.64, 6.35, 6.61, 6.89, 6.96, 7.06, 7.13-7.36.

Example 74 (16): 3- [2-[(E, 3R) -3-hydroxy-5- [3- (pyridin-2-ylsulfonylamino) phenyl] penta-4-enoxy] phenyl] propanoate TLC : Rf 0.36 (ethyl acetate);
^{1 1} H-NMR (CDCl ₃ ): δ 2.06-2.23, 2.72, 3.02, 4.16, 4.60, 6.31, 6.52, 6.86-6.93, 7.01, 7.10-7.22, 7.46, 7.85, 7.97, 8.41, 8.65.

Example 74 (17): 3- [2-[(E, 3R) -5- [3- (1-benzofuran-3-ylsulfonylamino) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propane Acid HPLC retention time (minutes): 0.98;
^{1 1} H-NMR (CDCl ₃ ): δ 2.08-2.13, 2.69, 2.96, 4.11, 4.55-4.62, 6.21, 6.52, 684-6.92, 6.99-7.03, 7.09-7.19, 7.30-7.40, 7.50, 7.70, 8.05.

Example 74 (18): 3- [2-[(E, 3R) -5-[3-[(4-butoxyphenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid TLC: Rf 0.40 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 0.95, 1.40-1.50, 1.68-1.79, 2.10-2.14, 2.68, 2.96, 3.93, 4.10-4.19, 4.60, 6.26, 6.52, 6.81-6.91, 6.97-7.09, 7.12- 7.24, 7.68.

Example 74 (19): 3- [2-[(E, 3R) -3-hydroxy-5- [3- (thiophene-3-ylsulfonylamino) phenyl] penta-4-enoxy] phenyl] propanoate TLC : Rf 0.35 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 2.10-2.15, 2.68, 2.96, 4.09-4.20, 4.62, 6.27, 6.54, 6.84-6.92, 7.00-7.23, 7.27-7.32, 7.86.

Example 74 (20): 3- [2-[(E, 3R) -3-hydroxy-5-[3-[(2-propylphenyl) sulfonylamino] phenyl] penta-4-enoxy] phenyl] propanoic acid TLC: Rf 0.38 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.00, 1.64-1.74, 2.10-2.15, 2.70, 2.93-3.01, 4.10-4.19, 4.60, 6.26, 6.53, 6.85-6.92, 7.02-7.06, 7.10-7.24, 7.33, 7.45, 7.95.

Example 74 (21): 3- [2-[(E, 3R) -5-[3-[(3-butylphenyl) sulfonylamino] phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid TLC: Rf 0.38 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 0.86, 1.18-1.28, 1.42-1.53, 2.08-2.14, 2.57, 2.69, 2.97, 4.10-4.21, 4.61, 6.25, 6.53, 6.84-6.92, 6.98, 7.04-7.21, 7.29-7.32, 7.55-7.60.

Example 75: 3- [2-[(3S) -5- [3- (cyclopentylsulfonylamino) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid 3- [2-[() used in Example 33 Example using the compound prepared in Example 74 (13) instead of E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid. By subjecting to the same operation as in 33, the following Example compounds were obtained.
HPLC retention time (minutes): 0.93;
^{1 1} H-NMR (CD ₃ OD): δ 1.55-1.63, 1.74-2.07, 2.52-2.56, 2.73, 2.84, 2.85-2.89, 3.53, 3.89, 4.09-4.19, 6.85, 6.93, 7.02, 7.08-7.19, 7.23 ..

Example 76: Methyl (R, E) -3-(2-((3-hydroxy-5-(3- (phenylsulfonamide) phenyl) penta-4-ene-1-yl) oxy) phenyl) propanoate Trimethylsilyldiazomethane (2.0 M hexane solution, 2.6 mL) was added to a solution of the compound (500 mg) prepared in Example 11 in methanol (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction solution under ice-cooling, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 1: 1) to give the title compound (495 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.03.

Example 77: Methyl 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] -3-oxopenta-4-enoxy] phenyl] propanoate of the compound (495 mg) prepared in Example 76. Manganese dioxide (868 mg) was added to a solution of dichloromethane (10 mL) at room temperature, and the mixture was stirred at the same temperature for 20 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 1: 1) to give the title compound (439 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.10.
^{1 1} H-NMR (CDCl ₃ ): δ 2.59-2.63, 2.88-2.92, 3.08-3.11, 3.68, 4.31-4.34, 6.80, 6.85-6.92, 7.12, 7.18-7.34, 7.42-7.56, 7.77-7.80.

Example 78: 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] -3-oxopenta-4-enoxy] phenyl] propanoic acid Methyl (R, E) used in Example 77 ) -3-(2-((3-Hydroxy-5- (3- (phenylsulfonamide) phenyl) penta-4-ene-1-yl) oxy) phenyl) propanoate, prepared in Example 11. By subjecting the compound to the same operation as in Example 77, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.97;
^{1 1} H-NMR (CD ₃ OD): δ 2.44-2.48, 2.81-2.85, 3.22, 3.25, 4.33-4.37, 6.82, 6.86, 6.97, 7.14-7.21, 7.29, 7.33-7.39, 7.48-7.52, 7.56-7.63 , 7.79-7.81.

Example 79: 3- [2- [5- [3- (benzenesulfonamide) phenyl] -3-oxopentoxy] phenyl] propanoic acid 3- [2-[(E, 3R)) used in Example 33 Instead of -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid, the compound prepared in Example 78 was used for the same purpose as in Example 33. By subjecting the operation, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.97;
^{1 1} H-NMR (CD ₃ OD): δ 2.47-2.51, 2.80-2.85, 2.88-2.91, 4.21-4.24, 6.85-6.95, 7.09-7.21, 7.44-7.48, 7.54, 7.74-7.76.

Example 80: 3- [2- [5- [3- (1-hydroxy-2-phenylethyl) phenyl] -3-oxopentoxy] phenyl] propanoic acid 3- [2- [2- [2-[] used in Example 78 (E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] The compound prepared in Example 12 (9) was used in place of propanoic acid. By subjecting to the same operation as in Example 78 → Example 79, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 2.48-2.52, 2.80-2.96, 3.03-3.08, 4.25, 4.82, 6.85-6.94, 7.08-7.22.

Example 81: Isopropyl 3- (2- (pent-4-in-1-yloxy) phenyl) propanoate in a solution of the compound (3.00 g) prepared in Example 1 in N, N-dimethylacetamide (25 mL) at room temperature. Cesium carbonate (9.39 g) was added at the same temperature, and the mixture was stirred at the same temperature for 15 minutes. 5-Chloro-1-pentyne (CAS Registry Number: 14267-92-6) (1.63 g) was added to the reaction solution at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 5: 1) to give the title compound (2.40 g) having the following physical characteristics.
HPLC retention time (minutes): 1.13.

Example 82: Isopropyl (E) -3- (2-((5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) penta-4-en-1-yl) Il) Oxy) Phenyl) Propanoate In a heptane (2 mL) solution of the compound (1.00 g) prepared in Example 81, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1. 17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to give the title compound (503 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.38.

Example 83: Isopropyl (E) -3-(2-((5- (3- (phenylsulfonamide) phenyl) penta-4-ene-1-yl) oxy) phenyl) propanoate The compound prepared in Example 82. In a solution of (180 mg) in THF (3 mL), the compound (168 mg) prepared in Example 9, chloro (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [ 2- (2'-Amino-1,1'-biphenyl)] palladium (II) (0.035 g) and a 2M tripotassium phosphate aqueous solution (0.67 mL) were added, and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1) to give the title compound (113 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.24.

Example 84: 3- [2-[(E) -5-[3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid

A 1 M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound (146 mg) prepared in Example 83 in THF (0.5 mL) and methanol (0.1 mL), and the mixture was stirred at 50 ° C. for 8 hours. It was acidified by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (105 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.10
^{1 1} H-NMR (CD ₃ OD): δ 1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45 -7.49, 7.55, 7.75-7.78.

Example 85: 3- [2-[(E) -5-[4- (1-hydroxy-2-phenylethyl) phenyl] penta-4-enoxy] phenyl] propanoic acid N-(used in Example 83 Example 83 → Example 84 using 1- (4-bromophenyl) -2-phenylethane-1-ol (CAS registration number: 20498-64-0) instead of 3-bromophenyl) benzenesulfonamide. By subjecting to the same operation as in the above, the following Example compounds were obtained.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 1.97-2.03, 2.41-2.45, 2.67-2.71, 2.96-3.03, 4.04, 4.86-4.90, 6.23-6.30, 6.44, 6.83-6.89, 7.16-7.34.

Example 86: 3- [2-[(E) -5-[3-[(1R) -1-hydroxy-2-phenylethyl] phenyl] penta-4-enoxy] phenyl] propanoic acid Used in Example 83 By using the compound prepared in Example 21 in place of the N- (3-bromophenyl) benzenesulfonamide obtained and subjecting it to the same operation as in Example 83 → Example 84, the compound has the following physical property values. The title compound was obtained.
HPLC retention time (minutes): 1.20;
^{1 1} H-NMR (CDCl ₃ ): δ 2.00, 2.43, 2.64-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.44, 6.83-6.89, 7.15-7.39.

Example 87: 3- [2-[(E) -5-[3-[(1S) -1-hydroxy-2-phenylethyl] phenyl] penta-4-enoxy] phenyl] propanoic acid Used in Example 21 (S) -Methyloxazaborolidin was used in place of (R) -methyloxazaborolidine, and the corresponding halide compound was used in place of the N- (3-bromophenyl) benzenesulfonamide used in Example 83. Then, by subjecting to the same operation as in Example 21 → Example 83 → Example 84, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.20;
^{1 1} H-NMR (CDCl ₃ ): δ 2.00, 2.44, 2.66-2.70, 2.95-3.07, 4.04, 4.89, 6.28, 6.45, 6.83-8.89, 7.15-7.40.

Examples 87 (1) to (10)
By using an amine compound corresponding to 3-bromoaniline used in Example 9 and subjecting it to the same operation as in Example 9 → Example 83 → Example 84, the title having the following physical property values is obtained. The compound was obtained.

Example 87 (1): 3- [2-[(E) -5- [3- (benzenesulfonamide) -2- (trifluoromethyl) phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (Minute): 1.08;
^{1 1} H-NMR (CDCl ₃ ): δ 1.92-1.99, 2.36-2.42, 2.64-2.68, 2.93-2.97, 3.99, 5.98, 6.02, 6.58-6.65, 6.81, 6.88, 7.00, 7.15-7.20, 7.39-7.45, 7.51-7.56, 7.65, 7.70-7.73.

Example 87 (2): 3- [2-[(E) -5- [5- (benzenesulfonamide) -2- (trifluoromethyl) phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (Minute): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 1.97-2.04, 2.43-2.49, 2.74-2.78, 3.00-3.04, 4.04, 6.25-6.32, 6.66, 6.85, 6.91, 7.10-7.25, 7.44-7.48, 7.53-7.58, 7.84-7.87.

Example 87 (3): 3- [2-[(E) -5- [3- (benzenesulfonamide) -5- (trifluoromethyl) phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (Minute): 1.11;
^{1 1} H-NMR (CDCl ₃ ): δ 1.96-2.02, 2.41-2.46, 2.72-2.76, 2.97-3.01, 4.03, 6.31-6.40, 6.84, 6.90, 7.15-7.25, 7.43-7.48, 7.52-7.57, 7.79- 7.82.

Example 87 (4): 3- [2-[(E) -5- [3- (benzenesulfonamide) -4- (trifluoromethyl) phenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (Minute): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 1.98-2.05, 2.45-2.50, 2.68-2.72, 2.97-3.01, 4.04, 6.36-6.47, 6.80-6.91, 7.15-7.22, 7.37-7.44, 7.51-7.55, 7.74- 7.79.

Example 87 (5): 3- [2-[(E) -5-[3- (benzenesulfonamide) -2-cyanophenyl] penta-4-enoxy] phenyl] propanoate HPLC retention time (minutes): 1.01;
^{1 1} H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.44-2.49, 2.64-2.68, 2.93-2.97, 4.01, 6.44, 6.60, 6.82, 6.88, 7.15-7.20, 7.31-7.32, 7.42-7.50, 7.52- 7.60, 7.82-7.85.

Example 87 (6): 3- [2-[(E) -5- [3- (benzenesulfonamide) -4-cyanophenyl] penta-4-enoxy] phenyl] propanoate HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 1.98-2.04, 2.46-2.51, 2.57-2.61, 2.92-2.96, 4.04-4.07, 6.38-6.46, 6.87, 6.92, 7.16-7.20, 7.24, 7.34, 7.49-7.55 , 7.60, 7.75-7.78.

Example 87 (7): 3- [2-[(E) -5- [3- (benzenesulfonamide) -2,4-dichlorophenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) : 1.07;
^{1 1} H-NMR (CD ₃ OD): δ 1.87-1.94, 2.36-2.41, 2.44-2.48, 2.81, 3.95, 6.25, 6.59, 6.74, 6.79, 7.03-7.08, 7.22, 7.39-7.43, 7.49-7.53, 7.67 -7.70.

Example 87 (8): 3- [2-[(E) -5- [3- (benzenesulfonamide) -4-methylsulfonylphenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 1.98-2.05, 2.46-2.50, 2.67-2.50, 2.77, 2.96-3.00, 4.03, 6.40-6.42, 6.84, 6.90, 7.16-7.22, 7.47-7.52, 7.58, 7.64, 7.71, 7.91-7.94.

Example 87 (9): 3- [2-[(E) -5- [3- (benzenesulfonamide) -5-methylsulfonylphenyl] penta-4-enoxy] phenyl] propanoic acid HPLC retention time (minutes) : 0.99;
^{1 1} H-NMR (CDCl ₃ ): δ 1.97-2.03, 2.44-2.49, 2.72-2.76, 2.97-3.03, 4.04, 6.36, 6.41-6.48, 6.84, 6.90, 7.15-7.22, 7.40, 7.45-7.49, 7.54- 7.58, 7.77, 7.82-7.84.

Example 87 (10): 3- [2-[(E) -5- [3- (benzenesulfonamide methyl) phenyl] penta-4-enoxy] phenyl] propanoate HPLC retention time (minutes): 1.10. ;
^{1 1} H-NMR (CDCl ₃ ): δ 1.96-2.02, 2.39-2.44, 2.66-2.70, 2.93-2.97, 4.03, 4.12, 5.33, 6.24, 6.36, 6.83-6.90, 6.96-6.99, 7.14-7.21, 7.47- 7.52, 7.54-7.59, 7.84-7.88.

Examples 88 (1)-(2)
By substituting the corresponding halide compound for the N- (3-bromophenyl) benzenesulfonamide used in Example 83 and subjecting it to the same operation as in Example 83 → Example 35 → Example 84. The title compound having the following physical property values was obtained.

Example 88 (1): 3- [2- [5- [3- (1-hydroxy-2-phenylethyl) phenyl] pentoxy] phenyl] propanoate TLC: Rf 0.61 (hexane: ethyl acetate = 1: 1) 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.47-1.55, 1.67-1.74, 1.79-1.85, 2.58, 2.65, 2.88, 2.97-3.07, 3.96, 4.89, 6.79-6.88, 7.09-7.33.

Example 88 (2): 3- [2- [2- [5- [4- (1-hydroxy-2-phenylethyl) phenyl] pentoxy] phenyl] propanoate HPLC retention time (minutes): 1.1;
^{1 1} H-NMR (CDCl ₃ ): δ 1.47-1.80, 2.48-2.56, 2.64-2.69, 2.82-2.88, 3.02-3.06, 3.95, 4.89-4.93, 6.79-6.87, 7.11-7.34.

Example 89: (R) -3- [2- [5- [3- (1-hydroxy-2-phenylethyl) phenyl] pentoxy] phenyl] propanoic acid, or (S) -3- [2- [5] -[3- (1-Hydroxy-2-phenylethyl) phenyl] pentoxy] phenyl] propanoic acid The compound prepared in Example 88 (1) was prepared from SFC (column used: Daicel Co., Ltd. CHIRALPAK-IF (10 mm × 250 mm), Optical division was performed using mobile phase: CO ₂ : acetonitrile: methanol = 75: 22.5: 2.5, flow velocity: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.). The optically active substance of Example 88 (1) obtained under the above optical resolution conditions was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IF (10 mm × 250 mm), mobile phase: CO ₂ : acetonitrile: methanol = 75: 22. As a result of analysis at 5: 2.5, flow velocity: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.), the retention times of the first peak and the second peak were 14.9 minutes and 19. It was one minute.

Example 90: N, O-dimethylhydroxyl in a solution of 4-bromo-N-methoxy-N-methylthiazole-2-carboxamide 4-bromothiazole-2-carboxylic acid (1.0 g) in dichloromethane (9.6 mL). Amine hydrochloride (609 mg) and diisopropylethylamine (2.5 mL) and 1- (chloro-1-pyrrolidinyl methylene) pyrrolidinium hexafluorophosphate (2.4 g) were added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (1.0 g) having the following physical characteristics.
TLC: Rf 0.3 (hexane: ethyl acetate = 2: 1).

Example 91: 1- (4-Bromothiazole-2-yl) -2-phenylethane-1-one In a solution of the compound (300 mg) prepared in Example 90 in diethyl ether (1 mL), benzylmagnesium bromide (0. 1M diethyl ether solution (40 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (181 mg) having the following physical characteristics.
TLC: Rf 0.7 (hexane: ethyl acetate = 4: 1).

Example 92: 3- [2-[(E) -5-[2- (1-hydroxy-2-phenylethyl) -1,3-thiazole-4-yl] penta-4-enoxy] phenyl] propanoic acid Instead of the 1- (3-bromophenyl) -2-phenylethanone used in Example 21, the compound prepared in Example 91 was used in place of the (R) -methyloxazaborolidine used in Example 21. Example 21 → Example 83 → Example 84 using (RS) -methyloxazaborolidine in place of the N- (3-bromophenyl) benzenesulfonamide used in Example 83 with a corresponding halide compound. By subjecting the same operation to the above, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.98;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.92-2.00, 2.41-2.48, 2.80-2.84, 2.85-2.90, 3.10-3.15, 4.01-4.06, 4.80-4.85, 5.83, 6.60-6.72, 6.85, 6.95, 7.14-7.18, 7.21-7.25.

Example 93: 3- [2-[(E) -5-[4- (1-hydroxy-2-phenylethyl) -1,3-thiazole-2-yl] penta-4-enoxy] phenyl] propanoic acid Equivalent to 2-bromothiazole-4-carboxylic acid in place of 4-bromothiazole-2-carboxylic acid used in Example 90, instead of N- (3-bromophenyl) benzenesulfonamide used in Example 83. Example 90-> Example 91-> Example 21 (where (RS) -methyloxazaborolidine is used instead of (R) -methyloxazaborolidine)-> Example 83-> By subjecting to the same operation as in Example 84, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 1.98-2.05, 2.41-2.47, 2.66-2.70, 2.96-3.00, 3.08, 3.34, 4.03, 5.18, 6.42-6.46, 6.58, 6.62, 6.83-6.89, 6.93, 7.16- 7.25, 7.27-7.34.

Example 94: 3- [2- [5- [5- (1-hydroxy-2-phenylethyl) -1,3-thiazole-2-yl] pentoxy] phenyl] propanoic acid Isopropyl 3 used in Example 35 -(2-((((R, E) -3-hydroxy-5-(3-((R) -1-hydroxy-2-phenylethyl) phenyl) penta-4-ene-1-yl) oxy) phenyl ) The following compound of Example was obtained by subjecting to the same operation as in Example 35 using the compound prepared in Example 93 instead of propanoate.
HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CDCl ₃ ): δ 1.56-1.64, 1.80-1.90, 2.57-2.61, 2.94, 3.05, 3.09-3.11, 3.96, 5.14, 6.80, 6.86, 7.14-7.25, 7.29-7.33, 7.46.

Example 95: 3- [2- [5- [2- (1-hydroxy-2-phenylethyl) -1,3-thiazole-5-yl] pentoxy] phenyl] propanoic acid Isopropyl 3 used in Example 35 -(2-((((R, E) -3-hydroxy-5-(3-((R) -1-hydroxy-2-phenylethyl) phenyl) penta-4-ene-1-yl) oxy) phenyl ) The following compound of Example was obtained by subjecting to the same operation as in Example 35 using the compound prepared in Example 92 instead of propanoate.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 1.51-1.59, 1.68-1.85, 2.57-2.61, 2.84, 2.90, 3.09, 3.27, 3.97, 5.14, 6.81, 6.86, 7.13-7.25, 7.28-7.32, 7.39.

Example 95 (1): 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] -N-methylsulfonylpropanamide. To a solution of compound (100 mg) in DMF (1 mL) is added methanesulfonamide (102 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (124 mg) and DMAP (78.7 mg) at room temperature. The mixture was stirred for 23 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 0: 1) to give the title compound (80.7 mg) having the following physical characteristics. HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 1.97-2.04, 2.37-2.42, 2.64-2.67, 2.96-2.99, 3.19, 4.05, 6.22, 6.33, 6.73, 6.85-6.92, 7.06-7.08, 7.13-7.17, 7.21, 7.41-7.45, 7.50-7.54, 7.76-7.78.

Example 95 (2): 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanamide 3- [2- [2-] used in Example 31 [(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] Example 31 using the compound prepared in Example 84 instead of propanoic acid. By subjecting to the same operation as in the above, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.98;
^{1 1} H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.40-2.45, 2.60-2.64, 3.03-3.07, 4.04, 5.55, 5.82, 6.29, 6.34-6.41, 6.86, 6.89-6.95, 7.03-7.06, 7.11- 7.22, 7.41-7.44, 7.49-7.53, 7.82-7.85, 8.25.

Example 95 (3): N- [3-[(E) -5- [2- (2-cyanoethyl) phenoxy] penta-1-eneyl] phenyl] benzenesulfonamide The compound prepared in Example 95 (2). Pyridine (0.052 mL) and trifluoroacetic anhydride (67.8 mg) were added to a solution of (100 mg) in THF (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Methanol and 1M aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to give the title compound (91.0 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.37-2.42, 2.61-2.65, 2.95-2.99, 4.03, 6.20, 6.34, 6.49, 6.84-6.94, 7.05-7.25, 7.41-7.46, 7.51-7.55, 7.75-7.78.

Example 95 (4): N- [3-[(E) -5- [2- [2- (1H-tetrazol-5-yl) ethyl] phenoxy] penta-1-enyl] phenyl] benzenesulfonamide
Trimethylsilyl azide (44.0 mg) and dibutyl tin oxide (24.0 mg) were added to a toluene (0.5 mL) solution of the compound (43.0 mg) prepared in Example 95 (3), and the mixture was stirred at 100 ° C. overnight. did. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate: methanol = 50: 50: 3 → 0: 100: 3) to give the title compound (15.0 mg) having the following physical properties.
HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CDCl ₃ ): δ 1.92-1.99, 2.34-2.39, 3.11-3.15, 3.30-3.34, 4.02, 6.20, 6.30, 6.83-6.90, 7.30-7.22, 7.39-7.43, 7.49-7.53, 7.76- 7.78.

Example 95 (5): Isobutyl (E)-(3- (5- (2- (3-amino-3-oxopropyl) phenoxy) penta-1-ene-1-yl) phenyl) (phenylsulfonyl) carbamate Triethylamine (0.20 mL) and isobutylchloroformate (110 mg) were added to a solution of the compound (100 mg) prepared in Example 84 in THF (1 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 10 minutes. Ammonia (28% aqueous solution, 0.5 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1) to give the title compound (120 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.11.

Example 95 (6): N- [3-[(E) -5- [2- [2- (1H-1,2,4-triazole-5-yl) ethyl] phenoxy] penta-1-enyl] Phenyl] benzenesulfonamide To a DMF (0.2 mL) solution of the compound (120 mg) prepared in Example 95 (5), N, N-dimethylformamide dimethylacetal (0.5 mL) was added, and the mixture was stirred at 100 ° C. for 4 hours. did. The reaction solution was concentrated under reduced pressure, acetic acid (1 mL) and hydrazine monohydrate (0.1 mL) were added, and the mixture was stirred at 100 ° C. for 3 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 0: 1). A 2M aqueous sodium hydroxide solution (0.2 mL) was added to a solution of the obtained residue (48 mg) in methanol (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1 M aqueous sodium dihydrogen phosphate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: methanol = 50: 50: 3 → 0: 100: 3) to obtain the title compound (24.0 mg) having the following physical properties. rice field.
HPLC retention time (minutes): 0.90;
^{1 1} H-NMR (CDCl ₃ ): δ 1.95-2.02, 2.38-2.43, 3.08-3.18, 4.04, 6.22, 6.32, 6.84-6.89, 6.94-6.97, 7.02, 7.07-7.21, 7.39-7.43, 7.49-7.53, 7.67, 7.75-7.77, 8.04.

Example 96: Isopropyl (E) -3-(2-((4-hydroxy-6- (3- (phenylsulfonamide) phenyl) hexa-5-ene-1-yl) oxy) phenyl) propanoate Example 2 Example 2 → Example 3 → Example 4 → Example using 2- (3-bromopropyl) -1,3-dioxane instead of 2- (2-bromoethyl) -1,3-dioxane used in By subjecting to the same operation as in Example 5 → Example 7 → Example 8 → Example 10, a title compound having the following physical property values was obtained.
TLC: Rf 0.43 (hexane: ethyl acetate = 1: 1).

Example 97: 3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enoxy] phenyl] propanoic acid Propane-2- used in Example 11 Il 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] The compound prepared in Example 96 was used instead of propanoate. By subjecting to the same operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CDCl ₃ ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.

Example 98: Isopropyl (R, E) -3-(2-((4-hydroxy-6- (3- (phenylsulfonamide) phenyl) hexa-5-ene-1-yl) oxy) phenyl) propanoate, Or isopropyl (S, E) -3-(2-((4-hydroxy-6- (3- (phenylsulfonamide) phenyl) hexa-5-ene-1-yl) oxy) phenyl) propanoate in Example 96. The produced compound was SFC (column used: Dycel Co., Ltd. CHIRALPAK-IC (20 mm × 250 mm), mobile phase: CO ₂ : methanol = 85:15, flow velocity: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: Optical division was performed using 35 ° C.). The optically active substance of Example 96 obtained under the above optical resolution conditions was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IC (10 mm × 250 mm), mobile phase: CO ₂ : methanol = 85:15, flow velocity: 30 mL / min. As a result of analysis at pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C., the retention times of the first peak and the second peak were 13.6 minutes and 15.8 minutes, respectively.

Example 99: (R) -3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enoxy] phenyl] propanoic acid, or (S)- 3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enoxy] phenyl] propanoic acid Propane-2-yl 3-[used in Example 11 The first peak optically active compound prepared in Example 98 instead of 2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate. By subjecting to the same operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CDCl ₃ ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.

Example 100: (R) -3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enoxy] phenyl] propanoic acid, or (S)- 3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enoxy] phenyl] propanoic acid Propane-2-yl 3-[used in Example 11 The second peak optically active compound prepared in Example 98 instead of 2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate. By subjecting to the same operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CDCl ₃ ): δ 1.82-1.95, 2.67-2.71, 2.98-3.02, 3.97-4.04, 4.36-4.40, 6.20, 6.52, 6.83, 6.87-6.91, 7.00-7.04, 7.10-7.21, 7.40- 7.45, 7.49-7.54, 7.66, 7.78-7.81.

Example 101: 3- [2- [6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhexoxy] phenyl] propanoic acid 3- [2-[(E, 3R) used in Example 33) Using the compound prepared in Example 97 instead of −5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid, the same operation as in Example 33. The title compound having the following physical property values was obtained by subjecting to.
HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CDCl ₃ ): δ 1.58-1.67, 1.72-2.00, 2.65-2.09, 2.93-3.07, 3.59-3.65, 3.95-4.05, 6.82-6.93, 6.98-7.01, 7.12-7.22, 7.40-7.45, 7.50-7.54, 7.77-7.80.

Example 102: (R) -3- [2- [2- [6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhexoxy] phenyl] propanoic acid, or (S) -3- [2- [6] -[3- (Benzenesulfonamide) phenyl] -4-hydroxyhexoxy] phenyl] propanoic acid The compound prepared in Example 101 was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IB (20 mm x 250 mm), mobile phase: Optical division was performed using CO ₂ : acetonitrile: methanol = 80: 18: 2, flow velocity: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.). The optically active substance of Example 101 obtained under the above optical resolution conditions was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IB (20 mm × 250 mm), mobile phase: CO ₂ : acetonitrile: methanol = 80: 18: 2, flow velocity. : 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column temperature: 35 ° C.), the retention times of the first peak and the second peak were 9.6 minutes and 12.3 minutes, respectively.

Example 103: 3- [2- [6- [3- (benzenesulfonamide) phenyl] -4-oxohexoxy] phenyl] propanoic acid 3- [2-[(E, 3R) -5) used in Example 78 -[3- (Benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] Using the compound prepared in Example 97 instead of propanoic acid, the same purpose as in Example 78 → Example 79. The title compound having the following physical property values was obtained by subjecting to the above operation.
TLC: Rf 0.45 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 2.01-2.10, 2.61-2.75, 2.83, 2.96, 3.96, 6.78-6.82, 6.86-6.91, 6.96, 7.10, 7.14-7.21, 7.42, 7.51, 7.68-7.84.

Examples 104 (1)-(2)
Using a phenol compound corresponding to the isopropyl 3- (2-hydroxyphenyl) propanoate used in Example 81, the same operation as in Example 81 → Example 82 → Example 83 → Example 84 is performed. As a result, the following Example compounds were obtained.

Example 104 (1): 2- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] Acetic acid HPLC retention time (minutes): 1.01;
^{1 1} H-NMR (CDCl ₃ ): δ 1.89-1.96, 2.33-2.38, 3.67, 4.01, 6.14, 6.29, 6.68, 6.85-6.94, 7.00-7.28, 7.39-7.43, 7.48-7.52, 7.74-7.77.

Example 104 (2): 4- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] butanoic acid HPLC retention time (minutes): 1.07;
^{1 1} H-NMR (CDCl ₃ ): δ 1.93-2.00, 2.37-2.43, 2.70, 4.00, 6.21, 6.33, 6.82-6.92, 7.04-7.19, 7.40-7.44, 7.49-7.53, 7.75-7.78.

Examples 105 (1) to (3)
By using a halide compound corresponding to the 5-chloro-1-pentyne used in Example 81 and subjecting it to the same operation as in Example 81 → Example 82 → Example 83 → Example 84. The following Example compounds were obtained.

Example 105 (1): 3- [2-[(E) -4- [3- (benzenesulfonamide) phenyl] buta-3-enoxy] phenyl] propanoic acid HPLC retention time (minutes): 1.01;
^{1 1} H-NMR (CD ₃ OD): δ 2.52-2.56, 2.67-2.71, 2.88-2.92, 4.10-4.13, 6.31, 6.46, 6.86, 6.93-6.98, 7.09-7.20, 7.44-7.49, 7.52-7.57, 7.75 -7.78.

Example 105 (2): 3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] hexa-5-enoxy] phenyl] propanoate TLC: Rf 0.44 (hexane: ethyl acetate) = 1: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.65-1.76, 1.77-1.88, 2.25-2.31, 2.69-2.75, 2.99-3.05, 3.99, 6.18, 6.33, 6.83, 6.89, 6.95-7.00, 7.10-7.21, 7.44, 7.53, 7.67, 7.81.

Example 105 (3): 3- [2-[(E) -7- [3- (benzenesulfonamide) phenyl] hepta-6-enoxy] phenyl] propanoate TLC: Rf 0.44 (hexane: ethyl acetate) = 1: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.61-1.73, 1.77-1.88, 2.27, 2.76-2.82, 3.02-3.07, 4.01, 6.29-6.33, 6.83-6.93, 7.08-7.23, 7.45, 7.53, 7.84, 8.75.

Example 106: Methyl 3- (2-((4-hydroxy-5-(3- (phenylsulfonamide) phenyl) pentyl) oxy) phenyl) propanoate Ethyl acetate (1 mL) of the compound (200 mg) prepared in Example 84 ) Dissolved. Methanol (1 mL) and trimethylsilyldiazomethane (2M hexane solution, 0.3 mL) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (2 mL). Saturated aqueous sodium bicarbonate solution (2 mL) and meta-chloroperbenzoic acid (171 mg) were added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL), 5% palladium-carbon (20 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After filtering the reaction solution, the filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 70: 30 → ethyl acetate) to give the title compound having the following physical property values. 53 mg) was obtained.
TLC: Rf 0.31 (hexane: ethyl acetate = 1: 1).

Example 107: 3- [2- [5- [3- (benzenesulfonamide) phenyl] -4-hydroxypentoxy] phenyl] propanoic acid Propane-2-yl 3- [2- [2-[] used in Example 11 (E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] The compound prepared in Example 106 was used instead of propanoate in the same manner as in Example 11. The title compound having the following physical property values was obtained by subjecting to the desired operation of.
TLC: Rf 0.60 (ethyl acetate);
^{1 1} H-NMR (CDCl ₃ ): δ 1.50-1.68, 1.68-1.74, 1.77-2.00, 2.61-2.70, 2.72-2.79, 2.92-2.99, 3.87, 3.95-4.05, 6.82-7.03, 7.15-7.21, 7.38- 7.45, 7.48-7.53, 7.77.

Example 108: Ethyl 3- (2- (4-oxobutyl) phenyl) propanoate of ethyl 3- [2- (4-hydroxybutyl) phenyl] propanoate (CAS Registry Number: 864677-94-1) (0.56 g). Sodium hydrogen carbonate (0.56 g) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (CAS Registry Number) in a solution of dichloromethane (9 mL) : 87413-09-0) (1.13 g) was added at 0 ° C. and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium thiosulfate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (0.34 g) having the following physical characteristics.
TLC: Rf 0.30 (hexane: ethyl acetate = 4: 1).

Example 109: 3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enyl] phenyl] propanoic acid Isopropyl 3-(used in Example 4 Example 4 → Example 5 → Example 7 → Example 8 → Example 10 → Same as Example 11 using the compound prepared in Example 108 instead of 2- (3-oxopropoxy) phenyl) propanoate. The title compound having the following physical property values was obtained by subjecting to the desired operation.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 1.60-1.79, 2.66-2.72, 2.97-3.01, 4.30-4.35, 6.16, 6.49, 6.98-7.07, 7.13-7.17, 7.40-7.53, 7.77-7.79.

Example 110: (R) -3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enyl] phenyl] propanoic acid, or (S)- 3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enyl] phenyl] propanoic acid

The compound produced in Example 109 was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IC (20 mm × 250 mm), mobile phase: CO ₂ : methanol = 85:15, flow velocity: 100 mL / min, pressure: 120 bar, wavelength: 220 nm. , Column temperature: 35 ° C.) was used for optical resolution. The optically active substance of Example 109 obtained under the above optical resolution conditions was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IC (10 mm × 250 mm), mobile phase: CO ₂ : methanol = 85:15, flow velocity: 30 mL / min. As a result of analysis at pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C., the retention times of the first peak and the second peak were 12.4 minutes and 14.4 minutes, respectively.

Example 111: 3- [2- [6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhexyl] phenyl] propanoic acid 3- [2-[(E, 3R)-] used in Example 33 Using the compound prepared in Example 109 in place of 5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid, for the same operation as in Example 33. By attaching, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CD ₃ OD): δ 1.37-1.61, 2.39-2.58, 2.84, 6.79-6.81, 6.98-7.08, 7.30-7.42, 7.61-7.63.

Example 112: 3- [2- [6- [3- (benzenesulfonamide) phenyl] -4-oxohexyl] phenyl] propanoic acid

Example 109 instead of 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid used in Example 78 By subjecting the compound produced in (1) to the same operation as in Example 78 → Example 79, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 1.75-1.83, 2.44-2.47, 2.54-2.61, 2.65-2.69, 2.75-2.79, 2.92-2.96, 6.90-6.94, 7.09-7.14, 7.18, 7.43-7.48, 7.54 , 7.74-7.76.

Example 113: Isopropyl 3- (2-((5- (3- (phenylsulfonamide) phenyl) penta-4-in-1-yl) oxy) phenyl) propanoate The compound prepared in Example 81 (1.5 g) ) And the compound (1.7 g) prepared in Example 9 in DMF (6 mL) solution, triethylamine (6 mL), bis (triphenylphosphine) palladium (II) dichloride (100 mg), copper (I) iodide (50 mg). ) Was added, and the mixture was stirred at 60 ° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 0: 1) to give the title compound (1.57 g) having the following physical characteristics.
TLC: Rf 0.39 (hexane: ethyl acetate = 2: 1).

Example 114: 3- [2- [5- [3- (benzenesulfonamide) phenyl] penta-4-inoxy] phenyl] propanoic acid Propane-2-yl 3- [2-[() used in Example 11 E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] The compound prepared in Example 113 was used in place of propanoate in the same manner as in Example 11. By subjecting to the desired operation, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CD ₃ OD): δ 2.06-2.12, 2.55-2.59, 2.64-2.67, 2.92-2.96, 4.13-4.16, 6.87, 6.95, 7.03-7.07, 7.12-7.20, 7.45-7.50, 7.56, 7.74 -7.77.

Example 115: Isopropyl (R) -3-(2-((5- (3- (phenylsulfonamide) phenyl) -3-((trimethylsilyl) oxy) penta-4-in-1-yl) oxy) phenyl ) Propanoate Using the compound prepared in Example 7 instead of the isopropyl 3- (2- (penta-4-in-1-yloxy) phenyl) propanoate used in Example 113, for the same purpose as in Example 113. By subjecting to the operation, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.12.

Example 116: Isopropyl (R) -3-(2-((3-hydroxy-5-(3- (phenylsulfonamide) phenyl) penta-4-in-1-yl) oxy) phenyl) propanoate Example 115 TBAF (1.0 M THF solution, 0.48 mL) was added to a THF (1 mL) solution of the compound (170 mg) prepared in (1) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → hexane: ethyl acetate = 1: 1) to give the title compound (82.8 mg) having the following physical properties.
HPLC retention time (minutes): 1.12.

Example 117: 3- [2-[(3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-inoxy] phenyl] propanoic acid Propane-2- used in Example 11 Il 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] The compound prepared in Example 116 was used in place of propanoate. By subjecting to the same operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.93;
^{1 1} H-NMR (CD ₃ OD): δ 2.19-2.30, 2.57-2.60, 2.91-2.95, 4.16-4.26, 4.85, 6.88, 6.96, 7.07-7.22, 7.46-7.51, 7.57, 7.75-7.77.

Example 118: 3- [2- [5- [3- (benzenesulfonamide) phenyl] pentoxy] phenyl] propanoic acid

Example 114 instead of 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid used in Example 33. By subjecting the compound produced in (1) to the same operation as in Example 33, a title compound having the following physical property values was obtained.
TLC: Rf 0.42 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 1.42-1.49, 1.58-1.65, 1.75-1.82, 2.55, 2.67, 2.95, 3.95, 6.80-6.97, 7.10-7.21, 7.27, 7.40, 7.49, 7.76.

Example 119: Isopropyl (Z) -3-(2-((5- (3- (phenylsulfonamide) phenyl) penta-4-en-1-yl) oxy) phenyl) propanoate The compound prepared in Example 113. A Lindlar catalyst (containing 5% by weight of palladium) (10.0 mg) and quinoline (12.8 mg) were added to a solution of (100 mg) in ethyl acetate (10 mL) at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere for 5 hours. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 1: 1) to give the title compound (92.3 mg) having the following physical properties.
HPLC retention time (minutes): 1.23.

Example 120: 3- [2-[(Z) -5-[3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid Propan-2-yl 3-[used in Example 11 Example using the compound prepared in Example 119 instead of 2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate. By subjecting to the same operation as in No. 11, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CD ₃ OD): δ 1.89-1.95, 2.37-2.43, 2.49-2.53, 2.83-2.87, 3.97-4.00, 5.74, 6.38, 6.83-6.89, 6.96-7.02, 7.13-7.19, 7.41-7.45 , 7.51, 7.72-7.76.

Example 121: 3- [2-[(Z, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid Isopropyl 3 used in Example 119 -(2-((5- (3- (Phenylsulfonamide) phenyl) penta-4-in-1-yl) oxy) phenyl) propanoate using the compound prepared in Example 116 in Example 119. → By subjecting to the same operation as in Example 11, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.92;
^{1 1} H-NMR (CD ₃ OD): δ 2.00-2.07, 2.44-2.48, 2.77-2.80, 4.02, 4.11, 4.75, 5.72, 6.46, 6.83-6.88, 6.92-7.04, 7.12-7.18, 7.42-7.47, 7.52 , 7.74-7.77.

Example 122: Ethyl (E) -3- (2- (3- (benzyloxy) -2-hydroxypropoxy) phenyl) acrylate Ethyl (E) -3- (2-hydroxyphenyl) propa-2-enoate (CAS) Registration number: 6236-62-0) (1.92 g) and diisopropylethylamine (0.69 mL) in a hexamethylphosphoramide (20 mL) solution, benzyl glycidyl ether (6.57 g) is added and the reaction mixture is heated to 80 ° C. Was stirred for 19 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (2.66 g) having the following physical characteristics.
TLC: Rf 0.33 (hexane: ethyl acetate = 2: 1).

Example 123: Ethyl (E) -3-(2- (3- (benzyloxy) -2-((tert-butyldimethylsilyl) oxy) propoxy) phenyl) acrylate The compound (300 mg) prepared in Example 122 and To a solution of imidazole (200 mg) in DMF (3 mL) was added tert-butyldimethylsilyl chloride (330 mg) at 0 ° C. and the reaction mixture was stirred at room temperature for 5 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give the title compound (380 mg) having the following physical characteristics.
TLC: Rf 0.41 (hexane: ethyl acetate = 9: 1).

Example 124: Ethyl 3- (2-(2-((tert-butyldimethylsilyl) oxy) -3-hydroxypropoxy) phenyl) propanoate Compound (380 mg) and 5% palladium carbon (50%) prepared in Example 123. A solution of wet (180 mg) in ethanol (8 mL) was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to give the title compound (290 mg) having the following physical characteristics.
TLC: Rf 0.34 (hexane: ethyl acetate = 4: 1).

Example 125: Ethyl 3- (2-(2-((tert-butyldimethylsilyl) oxy) -3-oxopropoxy) phenyl) propanoate of the compound (290 mg) and sodium hydrogen carbonate (190 mg) prepared in Example 124. To a solution of methylene chloride (3 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (390 mg) was added at 0 ° C., and the reaction mixture was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium thiosulfate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (250 mg) having the following physical characteristics.
TLC: Rf 0.40 (hexane: ethyl acetate = 4: 1).

Example 126: Ethyl (E) -3-(2-((2-Hydroxy-4- (3- (phenylsulfonamide) phenyl) but-3-ene-1-yl) oxy) phenyl) propanoate Example 45 Example 45 → Example 55 → Example using the compound prepared in Example 125 in place of (R) -4-((4-methoxybenzyl) oxy) -1-oxobutane-2-ylbenzoate used in. By subjecting to the same operation as in Example 56 → Example 116, a title compound having the following physical property values was obtained.
TLC: Rf 0.43 (hexane: ethyl acetate = 1: 1).

Example 127: 3- [2-[(E) -4- [3- (benzenesulfonamide) phenyl] -2-hydroxybut-3-enoxy] phenyl] propanoic acid

Instead of the propano-2-yl 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate used in Example 11. By subjecting the compound produced in Example 126 to the same operation as in Example 11, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76- 7.79.

Example 128: Ethyl (S, E) -3-(2-((2-hydroxy-4- (3- (phenylsulfonamide) phenyl) but-3-ene-1-yl) oxy) phenyl) propanoate, Or ethyl (R, E) -3-(2-((2-hydroxy-4- (3- (phenylsulfonamide) phenyl) but-3-ene-1-yl) oxy) phenyl) propanoate in Example 126. The produced compound was SFC (column used: Dycel Co., Ltd. CHIRALPAK-IB (20 mm × 250 mm), mobile phase: CO ₂ : 2-propanol = 83:17, flow velocity: 100 mL / min, pressure: 120 bar, wavelength: 220 nm, column. Optical division was performed using (temperature: 35 ° C.). The optically active substance of Example 126 obtained under the above optical resolution conditions was used as SFC (column used: Daicel Co., Ltd. CHIRALPAK-IB (10 mm × 250 mm), mobile phase: CO ₂ : 2-propanol = 83:17, flow velocity: 30 mL. As a result of analysis at / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 ° C.), the retention times of the first peak and the second peak were 12.6 minutes and 14.6 minutes, respectively.

Example 129: 3- [2-[(E) -4- [3- (benzenesulfonamide) phenyl] -2-hydroxybut-3-enoxy] phenyl] propanoic acid Propane-2- used in Example 11 The first peak prepared in Example 128 instead of yl 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate. The title compound having the following physical property values was obtained by subjecting to the same operation as in Example 11 using the optically active substance of.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76- 7.79.

Example 130: 3- [2-[(E) -4- [3- (benzenesulfonamide) phenyl] -2-hydroxybut-3-enoxy] phenyl] propanoic acid Propane-2- used in Example 11 The second peak prepared in Example 128 instead of yl 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate. The title compound having the following physical property values was obtained by subjecting to the same operation as in Example 11 using the optically active substance of.
HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 2.59-2.72, 2.93-3.08, 4.00, 4.17, 4.68-4.72, 6.40, 6.64, 6.84, 6.90-6.94, 7.03-7.07, 7.13-7.22, 7.38-7.52, 7.76- 7.79.

Example 131: Triethylamine (1.6 mL) and DMAP (177 mg) and benzene in a solution of N- (3-bromophenyl) -N- (phenylsulfonyl) benzenesulfonamide 3-bromoaniline (500 mg) in dichloromethane (10 mL). Sulfonyl anhydride (1.9 g) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (950 mg) having the following physical characteristics.
TLC: Rf 0.30 (hexane: ethyl acetate = 4: 1).

Example 132: N- (3- (4-Hydroxybuta-1-in-1-yl) phenyl) -N- (phenylsulfonyl) benzenesulfonamide DMF (4 mL) of the compound (949 mg) prepared in Example 131. To the solution was added triethylamine (1.5 mL) and 3-butin-1-ol (220 mg), copper iodide (40 mg) and bis (triphenylphosphine palladium) dichloride (147 mg), and the mixture was stirred at 80 ° C. for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (771 mg) having the following physical characteristics.
TLC: Rf 0.30 (hexane: ethyl acetate = 2: 1).

Example 133: N- (3- (4-Hydroxybutyl) phenyl) -N- (phenylsulfonyl) benzenesulfonamide Compound (600 mg) and 20% palladium hydroxide carbon (50% wet, 150 mg) prepared in Example 132. ) Was stirred at room temperature for 9 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to give the title compound (575 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.00.

Example 134: 3- [3- [4- [3- (benzenesulfonamide) phenyl] butoxy] phenyl] propanoic acid Methyl 3 in a solution of the compound (45 mg) prepared in Example 133 in THF (0.5 mL). -(3-Hydroxyphenyl) propanoate (22 mg) and DIAD (82 mg) and triphenylphosphine (40 mg) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. A 5N aqueous sodium hydroxide solution (0.4 mL) was added to the obtained residual methanol (0.5 mL) and 1,2-dimethoxyethane (0.5 mL) solution, and the mixture was stirred at 45 ° C. for 19 hours. 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (14 mg) having the following physical characteristics.
HPLC retention time (minutes): 0.97;
^{1 1} H-NMR (CDCl ₃ ): δ 1.66-1.75, 2.61, 2.74, 2.94, 3.94, 6.71-6.73, 6.79-6.86, 6.91-7.00, 7.14, 7.21, 7.37-7.41, 7.47-7.52, 7.72-7.74.

Examples 135 (1) to (6)
The following Example compounds were obtained by subjecting them to the same operation as in Example 134 using a phenol compound corresponding to the methyl 3- (3-hydroxyphenyl) propanoate used in Example 134.

Example 135 (1): 3- [4- [4- [3- (benzenesulfonamide) phenyl] butoxy] phenyl] propanoate HPLC retention time (minutes): 0.96;
^{1 1} H-NMR (CD ₃ OD): δ 1.64-1.74, 2.55-2.61, 2.86, 3.91, 6.80-6.84, 6.92-6.94, 7.11-7.15, 7.42-7.46, 7.50-7.54, 7.73-7.76.

Example 135 (2): 4- [2- [4- [3- (benzenesulfonamide) phenyl] butoxy] phenyl] butanoic acid HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 1.77-1.83, 1.96-2.03, 2.48, 2.60, 2.71-2.75, 3.97, 6.82, 6.87-6.90, 7.05-7.07, 7.11-7.20, 7.39-7.43, 7.47-7.52, 7.78-7.81.

Example 135 (3): 4- [3- [4- [3- (benzenesulfonamide) phenyl] butoxy] phenyl] butanoic acid HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CDCl ₃ ): δ 1.70-1.74, 1.95-2.02, 2.40, 2.59, 2.65, 3.93, 6.71-6.78, 6.86, 6.93-6.95, 7.12-7.21, 7.39-7.43, 7.48-7.52, 7.74- 7.77.

Example 135 (4): 2- [2- [2- [4- [3- (benzenesulfonamide) phenyl] butoxy] phenyl] acetic acid HPLC retention time (minutes): 0.94;
^{1 1} H-NMR (CDCl ₃ ): δ 1.68-1.72, 2.57, 3.65, 3.96, 6.80-6.94, 7.13, 7.21-7.24, 7.37-7.42, 7.47-7.52, 7.74-7.77.

Example 135 (5): 2- [3- [4- [3- (benzenesulfonamide) phenyl] butoxy] phenyl] acetic acid HPLC retention time (minutes): 0.95;
^{1 1} H-NMR (CDCl ₃ ): δ 1.74-1.77, 2.57-2.60, 3.66, 3.98, 6.83-6.86, 6.91-6.96, 7.11, 7.19-7.26, 7.36-7.43, 7.48-7.52, 7.75-7.78.

Example 135 (6): 3- [2- [4- [3- (benzenesulfonamide) phenyl] butoxy] phenyl] propanoate HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (CDCl ₃ ): δ 1.70-1.86, 2.61, 2.66-2.70, 2.97-3.01, 3.97, 6.82, 6.87-6.91, 7.03-7.06, 7.12-7.21, 7.40-7.44, 7.48-7.53, 7.60, 7.78-7.81.

Example 136: Isopropyl (E) -3-(2-((5- (3-nitrophenyl) -3-oxopenta-4-ene-1-yl) oxy) phenyl) propanoate N-used in Example 10 By using 3-bromonitrobenzene instead of (3-bromophenyl) benzenesulfonamide and subjecting it to the same operation as in Example 10 → Example 77, a title compound having the following physical property values was obtained.
TLC: Rf 0.43 (hexane: ethyl acetate = 2: 1).

Example 137: Isopropyl (E) -3-(2-((3,3-difluoro-5- (3-nitrophenyl) penta-4-ene-1-yl) oxy) phenyl) propanoate Produced in Example 136 The compound (205 mg) was dissolved in dichloromethane (0.4 mL), bis (2-methoxyethyl) aminosulfur trifluoride (1.5 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 → ethyl acetate) to give the title compound (29 mg) having the following physical characteristics.
TLC: Rf 0.66 (hexane: ethyl acetate = 2: 1).

Example 138: 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] -3,3-difluoropenta-4-enoxy] phenyl] propanoic acid Used in Example 55 (R). , E) -5-(2-((E) -3-methoxy-3-oxoprop-1-ene-1-yl) phenoxy) -1- (3-nitrophenyl) penta-1-en-3-yl By using the compound prepared in Example 137 instead of benzoate and subjecting it to the same operation as in Example 55 → Example 56 → Example 11, a title compound having the following physical property values was obtained.
TLC: Rf 0.22 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 2.50-2.62, 2.72, 2.93, 4.20, 6.30, 6.80-6.95, 7.05, 7.12-7.25, 7.43, 7.53, 7.78, 7.89.

Example 139: 3- [2- [5- [3- (benzenesulfonamide) phenyl] -3,3-difluoropentoxy] phenyl] propanoic acid

Example 138 instead of 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid used in Example 33. By subjecting the compound produced in (1) to the same operation as in Example 33, a title compound having the following physical property values was obtained.
TLC: Rf 0.20 (hexane: ethyl acetate = 1: 2);
^{1 1} H-NMR (CDCl ₃ ): δ 2.14-2.47, 2.67-2.74, 2.76-2.84, 2.88-2.98, 4.13-4.21, 6.79-6.88, 6.89-7.07, 7.11-7.25, 7.42, 7.52, 7.79.

Example 140: (S) -5-((2- (2,2-dimethyl-1,3-dioxolan-4-yl) ethyl) thio) -1-phenyl-1H-tetrazole 2-[(S)- 2,2-Dimethyl-1,3-dioxolane-4-yl] ethanol (CAS registration number: 32233-43-5) (2.00 g) in THF (25 mL) solution at room temperature 1-phenyl-1H-tetrazole -5-thiol (CAS registration number: 86-93-1) (3.66 g), triphenylphosphine (5.38 g) and DIAD (1.10 g) were added and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1) to give the title compound (4.14 g) having the following physical characteristics.
HPLC retention time (minutes): 0.97.

Example 141: (S) -5-((2- (2,2-dimethyl-1,3-dioxolan-4-yl) ethyl) sulfonyl) -1-phenyl-1H-tetrazole The compound prepared in Example 140. To a solution of (4.14 g) in acetonitrile (15 mL) and ethanol (15 mL), add ammonium molybdate tetrahydrate (1.57 g) and 30 wt% hydrogen peroxide solution (8.3 mL) under ice-cooling to room temperature. Was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 2,2-dimethoxypropane (8.3 mL), p-toluenesulfonic acid monohydrate (129 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1) to give the title compound (3.96 g) having the following physical characteristics.
HPLC retention time (minutes): 0.96.

Example 142: (S, E) -N- (3- (4,5-dihydroxypenta-1-ene-1-yl) phenyl) benzenesulfonamide 1 of the compound (1.04 g) prepared in Example 141. , 2-Dimethoxyethane (15 mL) solution was added potassium bis (trimethylsilyl) amide (0.5 M toluene solution, 15.3 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution, add a solution of N- (3-formylphenyl) benzenesulfonamide (CAS Registry Number: 151721-35-6) (800 mg) at −78 ° C. to 1,2-dimethoxyethane (5 mL), and add 1 at room temperature. Stirred for hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1). The obtained residue was dissolved in methanol (3 mL), 2 M hydrochloric acid (3 mL) was added at room temperature, and the mixture was stirred at 50 ° C. for 30 minutes. The reaction solution was ice-cooled, neutralized with 2M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 9: 1) to give the title compound (675 mg) having the following physical characteristics.
HPLC retention time (minutes): 0.73.

Example 143: (S, E) -1-hydroxy-5- (3- (phenylsulfonamide) phenyl) penta-4-en-2-ylbenzoate The compound (450 mg) and imidazole (131 mg) prepared in Example 142. ) To the DMF (5 mL) solution, t-butyldimethylchlorosilane (0.7M DMF solution, 2 mL) was added dropwise over 5 minutes under ice-cooling, and the mixture was stirred at room temperature for 24 hours. After cooling the reaction solution with ice, imidazole (131 mg) and t-butyldimethylchlorosilane (213 mg) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 mL), pyridine (0.42 mL), benzoyl chloride (215 mg) and DMAP (15.7 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. After cooling the reaction solution with ice, benzoyl chloride (215 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1). The obtained residue was dissolved in THF (3 mL) and acetic acid (0.30 mL), TBAF (1.0 M THF solution 1.6 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1) to give the title compound (292 mg) having the following physical characteristics.
HPLC retention time (minutes): 0.97.

Example 144: (S, E) -1-iodo-5- (3- (phenylsulfonamide) phenyl) penta-4-en-2-ylbenzoate DMF (1 mL) of the compound (147 mg) prepared in Example 143. ) To the solution was added imidazole (68.6 mg) and triphenylphosphine (106 mg) at room temperature. Iodine (102 mg) was added to the reaction solution under ice-cooling, and the mixture was stirred at 50 ° C. for 1.5 hours. After cooling the reaction solution with ice, triphenylphosphine (26.0 mg) and iodine (25.0 mg) were added, and the mixture was stirred at 50 ° C. for 30 minutes. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 3: 2) to give the title compound (121 mg) having the following physical properties.
HPLC retention time (minutes): 1.20.

Example 145: (S, E) -1- (2- (3-isopropoxy-3-oxopropyl) phenoxy) -5- (3- (phenylsulfonamide) phenyl) penta-4-en-2-yl Sodium hydride (60% in mineral oil, 13.1 mg) was added to a DMF (0.5 mL) solution of the compound (68.4 mg) prepared in Example 1 under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. .. A solution of the compound (60 mg) prepared in Example 144 at room temperature in DMF (0.5 mL) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and then purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 3: 2) to give the title compound (12.1 mg) having the following physical properties.
HPLC retention time (minutes): 1.29.

Example 146: 3- [2-[(E, 2S) -5- [3- (benzenesulfonamide) phenyl] -2-hydroxypenta-4-enoxy] phenyl] propanoic acid Used in Example 57 (R). , E) -5-(2-((E) -3-methoxy-3-oxoprop-1-ene-1-yl) phenoxy) -1-(3- (phenylsulfonamide) phenyl) penta-1-ene By using the compound prepared in Example 145 instead of -3-ylbenzoate and subjecting it to the same operation as in Example 57, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.95
^{1 1} H-NMR (CD ₃ OD): δ 2.50, 2.59-2.65, 2.95-2.99, 3.95-4.02, 4.09, 6.29, 6.43, 6.86-6.96, 7.08-7.10, 7.12-7.20, 7.44-7.48, 7.54, 7.75 -7.77.

Example 147: Cool a solution of 2- (3-nitrophenetoxy) acetate 2- (3-nitrophenyl) ethanol (CAS Registry Number: 52022-77-2) (2.00 g) in DMF (4 mL) to 0 ° C. Then, sodium hydride (60% in mineral oil, 0.7 g) was added, and the mixture was stirred at 0 ° C. for 15 minutes. Isopropylbromoacetate (2.6 g) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 2: 1) to obtain an ester compound (1.80 g). It was dissolved in methanol (15 mL), sodium hydroxide (2N aqueous solution, 10 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 2M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.15 g) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 3.05-3.07, 3.84-3.87, 4.14, 7.48, 7.58-7.60, 8.09-8.14.

Example 148: 2- (3-Nitrophenetoxy) ethane-1-ol A solution of the compound (1.15 g) prepared in Example 147 and 4-methylmorpholine (0.8 mL) in THF (10 mL) at 0 ° C. After cooling, isobutylchloroformate (0.8 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes, and the resulting white solid was collected by filtration. The filtrate was cooled to 0 ° C., sodium borohydride (1.15 g) was added, and the mixture was stirred at 0 ° C. for 10 minutes, then a small amount of water was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 1) to give the title compound (1.15 g) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 1.82, 3.00-3.03, 3.56-3.58, 3.69-3.78, 7.47, 7.56-7.58, 8.07-8.13.

Example 149: 3- [2- [2- [2- [3- (benzenesulfonamide) phenyl] ethoxy] ethoxy] phenyl] propanoic acid

The compound prepared in Example 148 in place of the (R, E) -5-hydroxy-1- (3-nitrophenyl) penta-1-en-3-ylbenzoate used in Example 54 was used in Example 54. Example 54 → Example 55 → Example 56 → Example 11 using the compound prepared in Example 1 in place of the methyl (E) -3- (2-hydroxyphenyl) propa-2-enoate used. By subjecting to the same operation, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 0.99;
^{1 1} H-NMR (DMSO-d ₆ ): δ 2.70-2.80, 3.17-3.18, 3.56-3.60, 3.68-3.71, 4.05-4.08, 6.84-6.96, 7.09-7.19, 7.50-7.60, 7.74-7.76.

Example 150: tert-butyl (S) -2- (3- (1-hydroxy-2-phenylethyl) phenyl) acetate (1S) -1- (3-bromophenyl) -2-phenyl-ethanol (412 mg) Add bromo- (2-tert-butoxy-2-oxo-ethyl) zinc (0.5M THF solution, 9 mL) and bis (tri-tert-butylphosphine) palladium (76 mg) to the solution of THF (0.5 mL). , 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (296 mg) having the following physical characteristics.
TLC: Rf 0.40 (hexane: ethyl acetate = 4: 1).

Example 151: tert-butyl 2-(3-((1S) -2-phenyl-1-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) phenyl) acetate The compound prepared in Example 150 ( To a solution of 296 mg) in dichloromethane (2 mL) was added 3,4-dihydro-2H-pyran (239 mg) and pyridinium 4-toluenesulfonate (71 mg), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (341 mg) having the following physical characteristics.
TLC: Rf 0.60 (hexane: ethyl acetate = 4: 1).

Example 152: 2-(3-((1S) -2-phenyl-1-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) phenyl) ethane-1-ol The compound prepared in Example 151. Water (0.15 mL) and lithium borohydride (187 mg) were added to a solution of (341 mg) in THF (4 mL), and the mixture was stirred at 40 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (236 mg) having the following physical characteristics.
TLC: Rf 0.50 (hexane: ethyl acetate = 1: 1).

Example 153: tert-Butyl 2-(3-((1S) -2-phenyl-1-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) phenetoxy) acetate The compound prepared in Example 152 ( To a 236 mg) solution of DMF (2 mL) was added tert-butyl bromoacetate (424 mg) and sodium hydride (60% in mineral oil, 87 mg), and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (250 mg) having the following physical characteristics.
TLC: Rf 0.60 (hexane: ethyl acetate = 4: 1).

Example 154: 2-(3-((1S) -2-phenyl-1-((tetrahydro-2H-pyran-2-yl) oxy) ethyl) phenetoxy) ethane-1-ol The compound prepared in Example 153. Water (0.1 mL) and lithium borohydride (123 mg) were added to a solution of (250 mg) in THF (0.5 mL), and the mixture was stirred at 40 ° C. for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (107 mg) having the following physical characteristics.
TLC: Rf 0.30 (hexane: ethyl acetate = 1: 1).

Example 155: Isopropyl (S) -3- (2- (2- (3- (1-hydroxy-2-phenylethyl) phenetoxy) ethoxy) phenyl) propanoate Dichloromethane (107 mg) of the compound (107 mg) prepared in Example 154. The compound (90 mg) prepared in Example 1, triphenylphosphine (114 mg) and 1,1- (azodicarbonyl) dipiperidin (110 mg) were added to the 1 mL) solution, and the mixture was stirred at room temperature for 1.5 hours. .. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain an ester compound (181 mg). Water (0.8 mL) and acetic acid (3.2 mL) were added to a solution of the obtained ester compound (181 mg) in THF (0.6 mL), and the mixture was stirred at 50 ° C. for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (97 mg) having the following physical characteristics.
TLC: Rf 0.20 (hexane: ethyl acetate = 4: 1).

Example 156: 3- [2- [2- [2- [3-[(1S) -1-hydroxy-2-phenylethyl] phenyl] ethoxy] ethoxy] phenyl] propanoic acid Propane used in Example 11- 2-Il 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] The compound prepared in Example 155 instead of propanoate. By subjecting to the same operation as in Example 11, the title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.10;
^{1 1} H-NMR (CDCl ₃ ): δ 2.59-2.63, 2.90-2.94, 3.00-3.03, 3.76-3.80, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 7.13-7.21, 7.22-7.32.

Example 157: 3- [2- [2- [2- [3-[(1R) -1-hydroxy-2-phenylethyl] phenyl] ethoxy] ethoxy] phenyl] propanoic acid Used in Example 150 (1S). ) -1- (3-Bromophenyl) -2-phenyl-ethanol, using the compound prepared in Example 21, Example 150 → Example 151 → Example 152 → Example 153 → Example 154 → By subjecting to the same operation as in Example 155 → Example 11, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.00;
^{1 1} H-NMR (CDCl ₃ ): δ 2.58-2.62, 2.90-2.95, 2.99-3.06, 3.77-3.81, 3.84-3.86, 4.10-4.13, 4.88, 6.82, 6.88, 7.13-7.21, 7.25-7.32.

Example 158: tert-butyl (trans-4- (3-hydroxypropyl) cyclohexyl) carbamate methyl trans-3- [4- (tert-butoxycarbonylamino) cyclohexyl] propanoate (500 mg) in THF (5 mL) is 0. The mixture was cooled to ° C., a solution of lithium borohydride (72.8 mg) in THF (1 mL) was added, and the mixture was stirred at room temperature for 15 minutes and at 50 ° C. for 3.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (429 mg) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 0.95-1.28, 1.44, 1.53-1.60, 1.75-1.78, 1.98-2.01, 2.27-2.31, 3.36, 3.62, 4.36.

Example 159: tert-butyl (trans-4- (3-oxopropyl) cyclohexyl) carbamate A solution of the compound (429 mg) prepared in Example 158 in dichloromethane (8.3 mL) was cooled to 0 ° C. and 1,1, 1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (848 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 1) to give the title compound (429 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 0.96-1.28, 1.44, 1.53-1.60, 1.62-1.75, 1.98-2.01, 2.42-2.46, 3.36, 4.38.

Example 160: Ethyl (E) -5- (trans-4-((tert-butoxycarbonyl) amino) cyclohexyl) penta-2-enoate ethyl diethylphosphonoacetate (747 mg) in THF (5 mL) at 0 ° C. After cooling, sodium hydride (60% in mineral oil, 145 mg) was added, and the mixture was stirred at 0 ° C. for 15 minutes. A solution of the compound (429 mg) prepared in Example 159 in THF (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 1: 1) to give the title compound (270 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00.

Example 161: Ethyl 5- (trans-4-((tert-butoxycarbonyl) amino) cyclohexyl) pentanoate Palladium on carbon (54 mg) was added to a solution of the compound (270 mg) prepared in Example 160 in ethanol (10 mL). The mixture was stirred at room temperature for one and a half hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure to give the title compound (282 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 0.95-1.38, 1.44, 1.53-1.59, 1.74-1.77, 1.98-2.01, 2.17-2.31, 3.36, 4.09-4.17, 4.35, 5.78-5.83, 6.91-7.00.

Example 162: tert-butyl (trans-4- (5-hydroxypentyl) cyclohexyl) carbamate A solution of the compound (282 mg) prepared in Example 161 in THF (5 mL) was cooled to 0 ° C. and lithium borohydride (36 mg). ) Was added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (270 mg) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 0.92-1.32, 1.44, 1.53-1.60, 1.73-1.78, 1.98-2.01, 2.26-2.31, 3.36, 3.64, 4.36.

Example 163: 5- (trans-4-aminocyclohexyl) pentane-1-ol hydrochloride Add hydrogen chloride (4.0 M dioxane solution, 6 mL) to the compound (140 mg) prepared in Example 162 and bring the reaction mixture to room temperature. After stirring for 1 and a half hours, the mixture was concentrated to give the title compound (180 mg) having the following physical properties.
^{1 1} H-NMR (DMSO-d ₆ ): δ 0.88-0.97, 1.15-1.42, 1.73-1.76, 1.90-1.93, 2.91, 3.36-3.75, 7.86.

Example 164: 5- (Trans-4- (Phenylsulfonamide) Cyclohexyl) Pentyl Benzene Sulfonate A solution of the compound (180 mg) pyridine (2 mL) and dichloromethane (2 mL) prepared in Example 163 was cooled to 0 ° C. and DMAP. (5 mg) was added. Benzenesulfonyl chloride (0.14 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (180 mg) having the following physical properties.
^{1 1} H-NMR (CDCl ₃ ): δ 0.84-0.89, 1.07-1.83, 3.04-3.09, 3.98-4.27, 7.51-8.07.

Example 165: Isopropyl 3- (2-((5- (trans-4- (phenylsulfonamide) cyclohexyl) oxy) phenyl) propanoate Compound (180 mg) prepared in Example 164 and 1-methyl-2- Cesium carbonate (377 mg) was added to a solution of pyrrolidinone (2 mL), and the reaction mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 2: 1) to give the title compound (60 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 0.83-0.92, 1.07-1.84, 2.53-2.57, 2.89-2.93, 3.04-3.12, 3.92-3.95, 4.26-4.27, 4.96-5.02, 6.79-6.86, 7.13-7.17, 7.48-7.59, 7.87-7.89.

Example 166: 3- [2- [5- [4- (benzenesulfonamide) cyclohexyl] pentoxy] phenyl] propanoic acid Propane-2-yl 3- [2-[(E, 3R) used in Example 11) Using the ester compound prepared in Example 165 instead of −5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoate, the same operation as in Example 11. The title compound having the following physical property values was obtained by subjecting to.
HPLC retention time (minutes): 1.20;
^{1 1} H-NMR (CDCl ₃ ): δ 0.83-0.92, 1.07-1.83, 2.64-2.68, 2.92-2.96, 3.05-3.13, 3.93-3.96, 4.42-4.43, 6.80-6.88, 7.14-7.20, 7.48-7.59, 7.87-7.89.

Examples of biological experiments are shown below, and the effects of the compounds of the present invention were confirmed based on these experimental methods.

Biological Experimental Example 1: In vitro test using Schwann cells (test method)
1) Preparation of rat Schwann cells The dorsal root ganglia (hereinafter abbreviated as DRG) of newborn rats 0 to 2 days old were excised in a clean bench and collected in DMEM. The collected tube was centrifuged at 400 g at room temperature for 3 minutes, the supernatant was removed, and a 0.25% collagenase solution was added. The extracted DRG was dispersed and separated by incubation at 37 ° C. for 30 minutes, and then centrifuged at 400 g at room temperature for 3 minutes. After removing the supernatant, 0.25% Trypsin / EDTA and DNase I were added. After incubation at 37 ° C. for 30 minutes, trypsin was inactivated with DMEM (10% FBS-DMEM) supplemented with 10% FBS, and 400 g was centrifuged at room temperature for 3 minutes. After removing the supernatant, 10% FBS-DMEM was added to prepare a cell suspension, which was passed through a filter (diameter 70 μm). The number of cells in the filtered cell suspension was counted ^{and prepared to 2.0 × 10 5} cells / mL, and then 100 μL / well was seeded on a poly-D-lysine coat 96-well black-clear plate. The _{cells were statically cultured in a CO 2} incubator under the conditions of 5% CO ₂ , 95% Air, and 37 ° C.
2) Compound addition The medium of the cell culture plate was removed by suction with an ejector, and DMEM supplemented with 1% dialyzed FBS and 100 μmol / L dibutyryl cyclic AMP was added. Then, a solution of the compound of the present invention dissolved in DMSO was added, and the _{cells were statically cultured in a CO 2} incubator under the conditions of 5% CO ₂ , 95% Air, and 37 ° C. The final concentration of the compound of the present invention in the cell culture plate well was 0.1, 0.3, 1 or 3 μmol / L.
3) Cell immunostaining Formaldehyde was added to each well of the cell culture plate 3 days after the compound treatment, and the cells were allowed to stand at room temperature for 30 minutes or more. After removing the supernatant, a 0.3% Triton X-100 solution was added, and the mixture was allowed to stand at room temperature for 20 minutes or longer. After removing the supernatant, a 5 μg / mL anti-myeline-associated glycoprotein antibody (anti-MAG antibody) solution was added, and the mixture was allowed to stand at room temperature for 60 minutes or longer or at 4 ° C. (tolerance range: 1 to 9 ° C.) overnight. After washing 3 times with 0.1% Triton X-100 solution, 10 μg / mL Alexa blue 488 anti-mouse IgG solution was added, and the mixture was allowed to stand at room temperature for 60 minutes or more or at 4 ° C. overnight. After washing 4 times with 0.1% Triton X-100 solution, 1 μg / mL Hoechst 33342 solution was added and the nuclei were stained.
(Evaluation method)
The MAG-positive area and the number of cell nuclei of the fluorescence image were calculated, and the sum of 5 visual fields / well was taken as the MAG-positive area and the number of cell nuclei of each well. Then, the value (MAG / cell nucleus value) obtained by dividing the MAG positive area of each well by the number of cell nuclei was calculated, and the Schwann cell differentiation promotion rate for the medium group was determined by the following formula.

(result)
The Schwann cell differentiation promotion rate (% of vehicle value) with respect to the medium group when 0.3 or 3 μmol / L of the compound solution of the present invention was added was as follows. From this, it is considered that the compound of the present invention has a strong neuroprotective and / or repairing action.

Biological Experimental Example 2: Test Using Streptozotocin-Induced Rat Model In order to evaluate the therapeutic effect of the compound of the present invention on diabetic peripheral neuropathy, an in vivo test using a streptozotocin model was performed.
(Test method)
1) Model preparation method A rat was prepared by intravenously administering 55 mg / kg of streptozotocin (hereinafter abbreviated as STZ).
2) Measurement of nociception threshold The rat was placed in a transparent acrylic cage for measurement at least once before STZ administration for 10 minutes or more, and the rat was acclimatized to the measurement environment. Eight von Frey filaments of 0.4, 0.6, 1, 2, 4, 6, 8, 15 g were applied vertically from under the wire mesh bed to the soles of the hind limbs. A quick escape reaction or a foot swing reaction was regarded as a positive reaction (with a reaction). The compound of the present invention was orally administered once a day from 14 to 28 days after STZ administration, and the dose was 0.03, 0.3, or 3 mg / kg. The nociception thresholds were before STZ administration, 14 days after STZ administration (dose start date of the compound of the present invention), 21 days (7 days after the start of dosing), 28 days (14 days after the start of dosing), and 35 days (drug suspension). After 7 days), the measurement was performed 2 hours after administration of the compound of the present invention.
(Evaluation method)
The nociception threshold was measured by the up-down method according to the method of Chaplan et al. (J Neuroscii Methods. 1994; 53: 55-63). The improvement rate of the nociception threshold was calculated based on the following formula.

(result)
The results of the nociception threshold when the compound of the present invention was administered at a dose of 0.3 mg / kg are shown in FIG. 1, and the improvement rate of the nociception threshold is shown in Table 2. All compounds showed a strong analgesic effect in peripheral neuropathy. Further, for example, in the compound of Example 11, improvement of the nociception threshold was observed from 7 days after the start of administration, and the action was sustained even 7 days after the drug suspension, and a continuous analgesic action was observed.

Biological Experimental Example 3: Reactive Metabolite Measurement Test A complex of the reactive metabolite of the compound of the present invention and quaternary gumlutathione (QA-GSH) was semi-quantified by LC / MS / MS (Soglia JR et al. , Chem. Res. Toxicol. 19 (3), 480-490, 2006), NADPH-dependent reactive metabolites were measured.

12.5 μL (final concentration: 1 mg / mL) of 20 mg / mL human liver microsomes (Xenotech) in 187.5 μL of 100 mM phosphate buffer (pH 7.4), and 25 μL (final concentration: 1 mmol / L) of 10 mmol / L QA-GSH. L), 0.5 mmol / L A solution of the compound of the present invention (DMSO: acetonitrile: water = 5: 38: 57) was added in an amount of 5 μL (final concentration of the compound of the present invention: 10 μmol / L). After pre-incubation in a water bath at 37 ° C. for 3 minutes, 20 μL (final concentration: 2 mmol / L) of 25 mmol / L NADPH was added to initiate the reaction. One hour after the reaction, 500 μL of acetonitrile containing QA-GS adduct internal standard substance (IS) was mixed to terminate the reaction. The complex (QA-GS adduct) of the reactive metabolite and QA-GS produced in the sample in which the reaction was stopped was analyzed by LC / MS / MS. Measurements were performed with the QA-GS adduct internal standard (IS).

The QA-GS adduct concentration was calculated from the following formula.

(result)
The QA-GS adduct concentration of the compound of the present invention was low, for example, the QA-GS adduct concentration of the compounds of Examples 11, 36, 37, 74 (13), 84 and 149 was 200 nmol / L or less. ..

Biological Experimental Example 4: Hand-1EST Test POCA® Hand1 -EST (DS) using the reproductive and developmental toxicity of the compound of the present invention as an index of the number of viable cells and the differentiation efficiency in the process of differentiation from mouse ES cells to myocardium. It was measured using Pharma Biomedical Co., Ltd. (Le Coz F et al., J. Toxicol., 40 (2): 251-61.2015).

A 1000 mg / mL DMSO solution of the compound of the present invention was prepared. A 1000 mg / mL DMSO solution of the compound of the present invention was diluted with a myocardial differentiation medium to prepare a 1000 μg / mL solution of the compound of the present invention (final concentration of DMSO 0.1%). While visually confirming the presence or absence of a precipitate, the cells were sequentially diluted 3-fold with a myocardial differentiation medium (final concentration of DMSO of 0.1%), and the concentration without a precipitate was recorded as the maximum solubility.

Thawed Hand1-ES cells (mouse ES cells in which the promoter region of the myocardial differentiation marker Hand1 gene and its downstream were transformed with the luciferase gene using pGL4.17 as a vector) were suspended in an undifferentiated maintenance medium and then gelatin-coated 60 mm Dish. Was sown and cultured for 2-3 days. After 2-3 days of culturing, trypsin-treated Hand1-ES cells were ^{subcultured in gelatin-coated 60 mm Dish at 2 × 10 6} cells / 5 mL and cultured overnight. Then, the trypsin-treated Hand1-ES cells were suspended in myocardial differentiation medium, seeded on a Prime Surface® U-bottom 96-well plate at 750 cells / 50 μL / well, and cultured for 2 hours. After 2 hours, 50 μL of myocardial differentiation medium containing the compound of the present invention or 5-FU which is a positive control was added (final concentration of the compound of the present invention: 1000, 333, 111, 37.0, 12.3, 4.12 and Final concentration of 1.37 μg / mL, 5-FU: 1,0.333, 0.111, 0.0370, 0.0123, 0.00412 and 0.00137 μg / mL, final concentration of DMSO: 0.1% ), Cultivated for 5 days. After exposure to the compound of the present invention or 5-FU for 5 days, CellTiter-Fluor® (Promega) was added to measure the viable cell number, and the excitation wavelength was used using a SpectraMax M5e plate reader (Molecular Fluorescent). Fluorescence at Ex 390 nm and fluorescence wavelength Em 505 nm was measured. Furthermore, Steady-Glo® (Promega) was added to measure the differentiation efficiency, and luminescence was measured using a SpectraMax M5e plate reader. The risk of teratogenicity was determined by inputting the obtained maximum solubility, 50% inhibition concentration of viable cell number, and 50% inhibition concentration of differentiation efficiency into the dedicated analysis software POCA Hand1-EST Analysis Software. The criteria for judgment were low risk for probability less than 0.52 and high risk for 0.52 or more (Nagahori et al., Toxicology Letters 259, 44-51).

(result)
Among the compounds of the present invention, for example, the compounds of Examples 84, 86 and 87 had a probability of less than 0.52 and were considered to have a low risk of teratogenicity.
[Formulation example]
Pharmaceutical example 1
Each of the following ingredients is mixed by a conventional method and then tableted to obtain 10,000 tablets containing 10 mg of the active ingredient in one tablet.
3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid ... 100 g
・ Carboxymethyl cellulose calcium… 20 g
・ Magnesium stearate… 10g
・ Microcrystalline cellulose… 870g

Pharmaceutical example 2
After mixing each of the following components by a conventional method, the mixture is filtered through a dust filter, filled in 5 ml ampoules, and heat sterilized in an autoclave to obtain 10,000 ampoules containing 20 mg of the active ingredient in one ampoule.
3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid ... 200 g
・ Mannitol… 20g
・ Distilled water ... 50L

The pharmaceutical composition containing the compound of the present invention has a strong neuroprotective and / or repairing action, and is therefore useful for the prevention and / or treatment of diseases associated with neuropathy.

Claims (22)

General formula (I)

[In the formula, R ¹ is (1) -R ^11- COOR ¹² , (2) -R ^13- CONR ¹⁴ R ¹⁵ , (3) -R ^17- CN, (4) -R ^18- CONHS (O). _2- R ¹⁹ , (5) -R ^20- CycD, or

(In the group, ring1 represents a 3- to 6-membered nitrogen-containing monocyclic saturated heterocycle, and R ¹⁰¹ is (1) a halogen atom, (2) a C1 to 4 alkyl group, or (3) a C1 to 4 haloalkyl group. , N represents an integer from 0 to 3, and when n is 2 or more, a plurality of R ^101s may be the same or different.)
R ¹¹ , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ , and R ²⁰ are independently (1) C1-6 alkylene groups, which may be substituted with 1 to 3 halogen atoms, (2). ) Represents a C2-6 alkenylene group optionally substituted with 1 to 3 halogen atoms, or (3) a C2-6 alkynylene group optionally substituted with 1 to 3 halogen atoms. When the alkylene group, alkenylene group or alkynylene group is a branched chain, two C1-2 alkyl groups branched from the same carbon atom may be combined to form a saturated carbon ring of C3-5.
R ¹² , R ¹⁴ , R ¹⁵ and R ¹⁹ independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, respectively.
CycD stands for triazole or tetrazole
R ² represents (1) a halogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group, p represents an integer from 0 to 3, and when p is 2 or more, a plurality of Rs. ² may be the same or different,
X represents (1) CH ₂ or (2) oxygen atom,
L ¹ is (1) a 1-4 ^R C3-7 alkylene group which may linear substituted with ^L1a, (2) a 1-4 ^R good linear be substituted with ^L1a C3~7 alkenylene group, optionally substituted by (3) 1-4 C3~7 alkynylene group which may straight optionally substituted with ^{R L1a} or (4) (1-2 ^{R L1a,} good represents a linear chain of C1~3 alkylene group) -O- (1 to 2 amino C1~3 alkylene group which may straight optionally substituted with ^{R L1a),}
R ^L1a is (1) halogen atom, (2) represents a hydroxyl group, a (3) an oxo group or (4) C1-2 alkyl group, ^a plurality of ^{R L1a} when ^{R L1a} is two or more the same or different from each other at best, further when the two R ^L1a each C1~2 alkyl groups attached to the same carbon atom, the C1~2 alkyl group saturated carbocyclic ring C3~5 together with the carbon atom bonded May form,

Represents a single bond, double bond or triple bond,
R ³ represents (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-2 alkyl group, or (5) a methylidene group, and q represents an integer from 0 to 2.

If is a single bond and q is 2, the plurality of R ^3s may be the same or different, and if at least one R ³ is a methyl group, together with the carbon atoms in the ^{adjacent L 1.} Cyclopropane may be formed,
CycA represents (1) C5-10 monocyclic or bicyclic carbocycles, or (2) 5-10 membered monocyclic or bicyclic heterocycles.
R ⁴ is (1) halogen atom, (2) hydroxyl, (3) C1 -4 alkyl group, (4) C1 -4 haloalkyl group, (5) C1 -4 alkoxy group, (6) C1 -4 haloalkoxy group, (7) a cyano group, or ₍₈₎ -SO 2 _-C1~2 alkyl group,, r represents an integer of 0 to 6, r is not different in the plurality of ^{R 4} when two or more identical respectively May be
L ² represents −R ³¹ −L ³ −R ^32-
L ³ is (1) -NR ^201- S (O)-, (2) -NR ^202- S (O) _2- , (3) -NR ^203- C (O)-, (4) -CR ²⁰⁴ Represents (OH)-, (5) -NR ^205- , (6) -S (O)-, or (7) -S (O) _2-
R ²⁰¹ , R ²⁰² , R ²⁰³ , R ²⁰⁴ , and R ²⁰⁵ each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, or (3) a C1-4 haloalkyl group. Among them, the alkyl group or haloalkyl group is substituted with (1) a hydroxyl group, (2) an oxo group, (3) a C3 to 6 monocyclic carbocycle, or (4) a 3 to 6 member monocyclic heterocycle. May be
R ³¹ and R ³² may each be independently substituted with (1) a bond or (2) 1-3 substituents selected from the group consisting of halogen atoms, hydroxyl groups and oxo groups. Represents a C1 to 3 alkylene group
CycB represents (1) C5-10 monocyclic or bicyclic carbocycles, or (2) 5-10 membered monocyclic or bicyclic heterocycles.
R ⁵ is (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkoxy group, (4) C2-6 alkynyl group, (5) C1-6 haloalkyl group, (6) C2. ~ 6 Haloalkenyl groups, (7) C2-6 haloalkynyl groups, (8) C1-6 alkoxy groups, or (9) C1-6 haloalkoxy groups, where t represents an integer from 0 to 6 and t is When it is 2 or more, the plurality of R ^5s may be the same or different. ], A pharmaceutical composition containing the compound or a salt thereof. In general formula (I),

But, (1) = CH- (1~2 amino ^R C2-6 alkylene group which may linear substituted with ^{L1a) -, (2) -} ( optionally substituted with one to two ^{R L1a} C3~7 alkylene group which may linear in) -, or (3) - (1-2 C1~3 alkylene group which may straight optionally substituted with ^{R L1a)} -O- (1-2 number of ^R C1 -3 alkylene group which may linear substituted with ^L1a) - is in ((1) ~ (3) R L1a represents the same meaning as in claim 1), according to claim 1 Pharmaceutical composition. The pharmaceutical composition according to claim 1 or 2, wherein R ¹ is −R ¹¹ −COOR ^12. The pharmaceutical composition according to any one of claims 1 to 3, wherein L ² is (1) -NR ^202- S (O) _2- or (2) -CR ²⁰⁴ (OH) -CH _2-. .. The pharmaceutical composition according to any one of claims 1 to 4, wherein CycA is a C5-6 monocyclic carbocycle. The pharmaceutical composition according to any one of claims 1 to 5, wherein CycB is a C5-6 monocyclic carbocycle. The general formula (I) is the general formula (I-1)

[In the formula, R ^11-1 represents a C2-4 alkylene group, L ^1-1 represents a linear C3-4 alkylene group optionally substituted with 1-2 R ^{L1a , CycA 1} and CycB ¹ are each independently a C5~6 monocyclic carbocyclic ^{ring, L 2-1} are, (1) -NH-S ( O) 2 -, or (2) -CH (OH) -CH 2 -, And other symbols have the same meaning as in claim 1. ], The pharmaceutical composition according to any one of claims 1 to 6. The pharmaceutical composition according to any one of claims 1 to 7, wherein X is an oxygen atom. The compound represented by the general formula (I) or a salt thereof
(1) 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(2) 3- [2-[(3S) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid,
(3) 3- [2-[(3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypentoxy] phenyl] propanoic acid,
(4) 3- [2-[(E, 3R) -5- [4- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(5) 3- [2-[(E, 3R) -5- [3- (cyclopentylsulfonylamino) phenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(6) 3- [2-[(E, 3R) -5- [3- (benzenesulfonamide) -2-methylphenyl] -3-hydroxypenta-4-enoxy] phenyl] propanoic acid,
(7) 4- [2-[(E, 3R) -5- [3- (benzenesulfonamide) phenyl] -3-hydroxypenta-4-enoxy] phenyl] butanoic acid,
(8) 3- [2-[(E) -4- [3- (benzenesulfonamide) phenyl] -2-hydroxybut-3-enoxy] phenyl] propanoic acid,
(9) (R) -3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enyl] phenyl] propanoic acid,
(10) (S) -3- [2-[(E) -6- [3- (benzenesulfonamide) phenyl] -4-hydroxyhex-5-enyl] phenyl] propanoic acid,
(11) 3- [2-[(E) -5-[3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid,
(12) 3- [2- [5- [3- (benzenesulfonamide) phenyl] pentoxy] phenyl] propanoic acid,
(13) 3- [2-[(3S) -3-hydroxy-5-[3-[(1R) -1-hydroxy-2-phenylethyl] phenyl] pentoxy] phenyl] propanoic acid,
(14) 3- [2-[(3S) -3-hydroxy-5-[3-[(1S) -1-hydroxy-2-phenylethyl] phenyl] pentoxy] phenyl] propanoic acid,
(15) 3- [2- [2- [2- [3- (benzenesulfonamide) phenyl] ethoxy] ethoxy] phenyl] propanoic acid,
(16) 3- [2- [6- [3- (benzenesulfonamide) phenyl] -4-oxohexyl] phenyl] propanoic acid, or (17) 3- [2- [5- [3- (benzenesulfonamide) benzenesulfon) The pharmaceutical composition according to claim 1, which is amide) phenyl] -3,3-difluoropentoxy] phenyl] propanoic acid or a salt thereof. The pharmaceutical composition according to any one of claims 1 to 9, for neuroprotection and / or repair. The pharmaceutical composition according to claim 10, wherein the neuroprotection and / or repair is glial cell-mediated neuroprotection and / or repair. The pharmaceutical composition according to claim 11, wherein the glial cell-mediated neuroprotection and / or repair is neuroprotection and / or repair by promoting myelination of Schwann cells. The pharmaceutical composition according to any one of claims 1 to 12, which is a prophylactic and / or therapeutic agent for neuropathy. The pharmaceutical composition according to claim 13, wherein the neuropathy is a peripheral neuropathy. Peripheral neuropathy includes chronic inflammatory demyelinating polyneuritis, Gillan Valley syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, peripheral neuropathy associated with chemotherapy drug administration , Or the pharmaceutical composition according to claim 14, which is a peripheral neuropathy associated with Charcot-Marie-Tooth disease. A Schwann cell differentiation promoter containing the compound represented by the general formula (I) according to claim 1 or a salt thereof. A neuroprotective and / or repair agent containing the compound represented by the general formula (I) according to claim 1 or a salt thereof. The agent of claim 17, wherein the neuroprotection and / or repair is glial cell-mediated neuroprotection and / or repair. The agent according to claim 18, wherein the glial cell-mediated neuroprotection and / or repair is neuroprotection and / or repair by promoting myelination of Schwann cells. A prophylactic and / or therapeutic agent for neuropathy containing the compound represented by the general formula (I) according to claim 1 or a salt thereof. The agent according to claim 20, wherein the neuropathy is a peripheral neuropathy. Peripheral neuropathy includes chronic inflammatory demyelinating polyneuritis, Gillan Valley syndrome, nodular periarteritis, allergic vasculitis, diabetic peripheral neuropathy, strangulation neuropathy, peripheral neuropathy associated with chemotherapy drug administration , Or the agent according to claim 21, which is a peripheral neuropathy associated with Charcot-Marie-Tooth disease.

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